Bicyclic compound

ABSTRACT

A compound represented by the general formula I: I wherein R1 represents hydrogen, etc. R 2  represents NHSO 2 R 3 , etc., provided that R 3  represents C 1-6  alkyl, etc. R 5  represents hydrogen, etc. R 6  and R 7  may be the same or different and each independently represents hydrogen, etc. X represents oxygen, etc. Y represents oxygen, etc. Z 1  to Z 6  each represents carbon, etc. n is an integer of 0 to 6 and ast1 indicates that the carbon atom is asymmetric, and *2, in the case where R 5  is not hydrogen, indicates that the carbon atom is asymmetric or a salt of the compound.

FIELD OF THE INVENTION

This invention relates to novel compounds which are useful as a medicinefor treating and preventing diabetes, obesity, hyperlipidemia, digestivediseases, depression, fatty liver or urinary incontinence.

BACKGROUND OF THE INVENTION

Beta-adrenoreceptors were classified into three classes,β1-adrenoreceptor, β2-adrenoreceptor and β3-adrenoreceptor, and it wasrecognized that stimulation of β1 induces an increase in the heart rateand stimulation of β2 induces a relaxation of the smooth muscle tissue,thereby resulting in lowering the blood pressure. It was also recognizedthat stimulation of β3 facilitates the lipolysis in adipocytes, therebyresulting in increasing the thermogenesis. Therefore, compounds havingβ3-agonist activity were shown to be useful as a medicine for treatingand preventing diabetes, obesity and hyperlipidemia (Nature, vol. 309,pp. 163-165, 1984; Int. J. Obes. Relat. Metab. Disord., vol. 20, pp.191-199, 1996; Drug Development Research, vol. 32, pp. 69-76, 1994, J.Clin. Invest., vol. 101, pp. 2387-2393, 1998). Recently, it was shownthat β3-adrenoreceptor is expressed in the detrusor and a β3-agonistinduces a relaxation of the detrusor (J. Urinol., vol. 161, pp. 680-685,1999; J. Pharmacol. Exp. Ther., vol. 288, pp. 1367-1373, 1999).Therefore, compounds having β3-agonist activity are expected to beuseful as a medicine for treating and preventing urinary incontinence.

Some compounds showing a β3-agonist activity have been known. Compoundshaving high selectivity or having low β1- and β2-stimulating activitiesare particularly required when their usefulness as a medicine is takeninto consideration. This is because compounds having both β1- andβ2-stimulating activities induce side effects such as increase in theheart rate and lowering of the blood pressure, as set forth above. Sofar, the following compounds have been exemplified as compounds relatingto β3:the compound (BRL 37344) having the following structural formuladescribed in EP 023385 and the literature (Drugs of the future, vol. 16,p. 797 (1991)):

the compound (CL 316,243) having the following structural formuladescribed in EP 0455006 and the literature (J. Med. Chem., vol. 35, p.3081 (1992)):

andthe compound having the following structural formula described in WO94/29290:

Further, EP 0659737 discloses a variety of compounds and specificallydescribes as an example in Example 1 in the text of specification thecompound having the following structural formula:

However, the chemical structures of the above compounds are clearlydistinct from those of the claimed compounds of the present invention.

In addition, the compound described in EP 171702 and having thefollowing structural formula:

has been known as having heart rate-increasing activity, myocardialcontraction enhancement and antiobestic activity. However, this compoundacts on the heart and is different from the compound of the presentinvention in the chemical structure and in that the former strongly actson the heart.

Further, the compound described in JP-A-55-53262 and JP-A-58-41860 andhaving the following structural formula:

is known as having α,β-blocking activity, namely the effect of loweringblood pressure; and the compound described in DE 2651572 and having thefollowing structural formula:

is known as having vasodilator action. However, these compounds aredifferent from the compounds of the present invention in their chemicalstructures and intended uses.

The present inventors formerly invented compounds having excellentβ3-agonist activity and disclosed compounds represented by, for example,the following structural formula in WO 97/25311.

The above compounds, however, are different from the compounds of thepresent invention in their chemical structures.

Further, the present inventors disclosed compounds represented by, forexample, the following structural formula in WO 01/83451.

DISCLOSURE OF THE INVENTION

There has been a need for a novel and useful P3-selective agonist whichcan be used for treating and preventing diabetes, obesity,hyperlipidemia, urinary incontinence and the like.

In order to solve the above problems, the present inventors synthesizeda variety of compounds and studied their activities. As a result, theinventions disclosed in the abovementioned WO 01/83451 was completed. Itwas thought, however, that there was a need to provide further usefulcompounds. The present inventors have earnestly studied and synthesizedmany more compounds. As a result, the present inventors have found thata novel bicyclic compound of the general formula (I) set forth below hasselective β3-agonist activity and that it can exhibit sufficienthypoglycemic and lipolytic activities with high safety and further hasanti-urinary incontinence activity due to a relaxation of the detrusor,then completed the present invention.

That is, the present invention includes the following inventions.

-   -   (1) A compound of the general formula (I):        or a salt thereof,        wherein    -   R¹ represents a hydrogen atom, a hydroxyl group or a halogen        atom;    -   R² represents NHSO₂R³ or SO₂NR R;    -   R³ represents a (C₁-C₆)alkyl group, a benzyl group, a phenyl        group or NR⁴R^(4′);    -   R⁴ and R^(4′) may be the same or different and each        independently represents a hydrogen atom or a (C₁-C₆)alkyl        group;    -   R⁵ represents a hydrogen atom or a (C₁-C₆)alkyl group;    -   R⁶ and R⁷ may be the same or different and each independently        represents a hydrogen atom, a (C₁-C₆)alkyl group, a (C₁-C₆)alkyl        group optionally substituted with one or more halogen atoms, an        optionally substituted —(CH₂)_(n)-phenyl group, —CH═CH—CO₂R⁵ or        —(CH₂)_(n)—R⁸;    -   R⁸ represents OR⁵, CN, NR⁴¹R^(41′), CO₂R⁵, SO₃R⁵,        SO₂(C₁-C₆)alkyl, SO₂NR⁴¹R^(41′), C(═O)R⁵, C(═O)NR⁴¹R^(41′) or        NR⁵¹COR⁵, wherein R⁵ is as defined above; R⁵¹ represents a        hydrogen atom or a (C₁-C₆)alkyl group; R⁴¹ and R^(41′) may be        the same or different and each independently represents a        hydrogen atom, a (C₁-C₆)alkyl group or a (C₃-C₆)cycloalkyl        group, or R⁴¹ and R^(41′) taken together represent a        (C₂-C₆)alkylene group; or R⁸ is a heterocycle selected from        pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,        imidazolyl, triazolyl, 1,2,4-oxadiazolyl, isoxazolyl,        tetrazolyl, pyrazolyl, hexamethyleneiminyl, piperidinyl and        pyrrolidinyl, wherein one of the ring nitrogen atoms of        imidazolyl, triazolyl and tetrazolyl may be optionally        substituted with a (C₁-C₆)alkyl group which is optionally        substituted with one or more halogen atoms; wherein with respect        to one or more of the ring carbon atoms of the each heterocycle,        each of them may be optionally substituted with one or more        substituents which are independently selected from hydrogen, a        (C₁-C₆)alkyl group optionally substituted with one or more        halogen atoms, a halogen atom, nitro, cyano and —(CH₂)_(n)—R⁹;        and wherein the ring nitrogen atom of hexamethyleneiminyl,        piperidinyl and pyrrolidinyl may be substituted with a        (C₁-C₆)alkyl group, a (C₃-C₆)cycloalkyl group, COR⁵, COOR⁵,        CONR⁴R^(4′) or SO₂R⁵;    -   R⁹ represents NR⁴R^(4′), CO₂R⁵, C(═O)—NR⁴R^(4′), OR⁵, SO₃R⁵,        SO₂(C₁-C₆)alkyl or SO₂NR⁴R^(4′), wherein R⁵, R⁴ and R^(4′) are        as defined above; provided that the combinations of R⁶ and R⁷        are excluded in which R⁶ and R⁷ are the same or different and        are each selected from a hydrogen atom, (C₁-C₆)alkyl and an        optionally substituted —(CH₂)_(m)-phenyl group wherein m is 0 or        1;    -   X represents NR¹⁰, an oxygen atom or a sulfur atom;    -   Y represents an oxygen atom, NH, a sulfur atom or a methylene        group;    -   all of Z¹ to Z⁶ represent a carbon atom; or one of them        represents a nitrogen atom and the others represent a carbon        atom;        provided that when Z¹ is a nitrogen atom, then R⁷ is absent;        when Z² is a nitrogen atom, then R⁶ is absent; and when any one        of Z³ to Z⁶ is a nitrogen atom, then no linkage is generated        between Y and the corresponding Z;    -   R¹⁰ represents a hydrogen atom, an optionally substituted        —(CH₂)_(n)-phenyl group, a —(C₁-C₁₀)alkyl group or        —(CH₂)_(n)—R⁸, wherein R⁸ is as defined above;    -   n is an integer of 0 to 6;    -   *1 represents an asymmetric carbon atom; and    -   *2 represents an asymmetric carbon atom when R⁵ is other than a        hydrogen atom.    -   (2) A compound as defined in the above (1) having the general        formula (I), wherein Z¹ is a nitrogen atom or a carbon atom; and        each of Z² to Z⁶ is a carbon atom, or a salt thereof.    -   (3) A compound as defined in the above (1) or (2) having the        general formula (I), wherein R⁸ is OR⁵, CN, NR⁴¹R^(41′), CO₂R⁵,        SO₃R⁵, SO₂(C₁-C₆)alkyl, SO₂NR⁴¹R^(41′), C(═O)R⁵ or        C(═O)NR⁴¹R⁴¹′, wherein R⁵ is as defined above; and R⁴¹ and        R^(41′) may be the same or different and are each independently        a hydrogen atom or a (C₁-C₆)alkyl group, or R⁴¹ and R^(41′)        taken together represent a (C₂-C₆)alkylene group; or R⁸ is a        heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl,        thiazolyl, oxazolyl, imidazolyl, triazolyl, 1,2,4-oxadiazolyl,        isoxazolyl, tetrazolyl and pyrazolyl, wherein one of the ring        nitrogen atoms of imidazolyl, triazolyl and tetrazolyl may be        optionally substituted with a (C₁-C₆)alkyl group which is        optionally substituted with one or more halogen atoms; wherein        with respect to one or more of the ring carbon atoms of the each        heterocycle, each of them may be optionally substituted with one        or more substituents which are independently selected from        hydrogen, a (C₁-C₆)alkyl group optionally substituted with one        or more halogen atoms, a halogen atom, nitro, cyano and        —(CH₂)_(n)—R⁹, wherein R⁹ is as defined above, or a salt        thereof.    -   (4) A compound as defined in the above (1) having the general        formula (I), wherein Z² is a nitrogen atom; R⁶ is absent; and        each of Z¹ and Z³ to Z⁶ is a carbon atom, or a salt thereof.    -   (5) A compound as defined in any one of the above (1) to (4)        having the general formula (I), wherein R¹ is present on para        position (2-position) with respect to the amino alcohol side        chain, or a salt thereof.    -   (6) A compound as defined in any one of the above (1) to (5)        having the general formula (I), wherein Y is an oxygen atom, NH        or a sulfur atom, or a salt thereof.    -   (7) A compound as defined in any one of the above (1) to (6)        having the general formula (I), wherein X is NH, an oxygen atom        or a sulfur atom, or a salt thereof.    -   (8) A compound as defined in any one of the above (1), (2) and        (4), which is a compound selected from the group consisting of:    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylic        acid;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylic        acid;    -   (R)-N-[3-[2-[2-(3-hydroxymethyl-2-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(N′,N′-dimethylamino)methyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acryl        ate;    -   (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylic        acid;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionate;    -   (R)-3-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionic        acid;    -   (R)-N-[3-[2-[2-[3-(2-aminoethyl)-2-methyl-1H-indol-6-yloxy]ethyl        amino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(2-N′,N′-dimethylamino)ethyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-acetyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]        acetic acid;    -   ethyl        (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethyl        amino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   (R)-[6-[2-[2-(4-hydroxy-3-methylsulfamoyl)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]        acetic acid;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]acetic        acid;    -   (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]propionic        acid;    -   (R)-N-[3-[2-[2-[2-(2-methoxyethyl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-ethyl-2-(2-methoxyethyl)-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylic        acid;    -   ethyl        (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;    -   ethyl        (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;    -   ethyl        (R,R)-6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]propoxy]-3-methyl-1H-indole-2-carboxylate;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]acetate;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]propionate;    -   (R)-N-[3-[2-[2-(2-pyrrolidylcarbonylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[2-(isoxazol-3-yl)benzofuran-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-5-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;    -   (R)-1-benzyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-1-[3-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-1-[4-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-N-[3-[2-[2-(2,3-ditrifluoromethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(3-ethyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-4-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[2-(N′-t-butyloxycarbonylpiperidin-3-yl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[1-hydroxy-2-(3-methyl-2-piperidin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(2-acetylaminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-3-[6-[2-[2-hydroxy-2-(3-methylsulfonylaminophenyl)ethylamino]ethoxy]-3-phenyl-1H-indol-2-yl]propionate;    -   (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-3-[6-[2-[2-(4-fluoro-3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]propionate;    -   (R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethyl]amino]ethoxy]-1H-indol-2-yl]-N,N-dimethylpropionamide;    -   ethyl        (R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]propionate;    -   ethyl        (R)-2-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]acetate;    -   (R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(3-methoxyindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;    -   (R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;    -   (R)—N-methyl-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamide;        and    -   (R,R)-N-[3-[1-hydroxy-2-[1-methyl-2-(3-methylindazol-6-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide,        or a salt thereof.    -   (9) A medicine comprising a compound defined in the above (1) or        a salt thereof as an active ingredient.    -   (10) A medicine as defined in the above (9), wherein the        medicine is for treating or preventing any one of diabetes,        obesity, hyperlipidemia and urinary incontinence.

Unless otherwise specified, “halogen atom” as used herein means afluorine atom, a chlorin atom, a bromine atom or an iodine atom. Inaddition, “(C₁-C₆)alkyl group” means a straight or branched saturatedhydrocarbon group containing from 1 to 6 carbon atoms and specificallymeans methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl or the like.“(C₃-C₆)cycloalkyl group” means a cyclic saturated hydrocarbon groupcontaining from 3 to 6 carbon atoms and specifically means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or the like.

R¹ represents a hydrogen atom, a hydroxyl group or a halogen atom.Examples thereof include a hydrogen atom, a hydroxyl group, a fluorineatom, a chlorine atom, a bromine atom and an iodine atom. Preferredexamples thereof include a hydrogen atom, a hydroxyl group, a fluorineatom, a chlorine atom and a bromine atom. Although the position on thebenzene ring at which R¹ is attached is not limited, the position ispreferably ortho- or para-position with respect to the aminoethanolside-chain, with para-position (2-position) being particularlypreferred.

R² represents NHSO₂R³ or SO₂NR⁴R^(4′), wherein R³ represents an alkylgroup containing from 1 to 6 carbon atoms, a benzyl group, a phenylgroup or NR⁴R^(4′) and wherein R⁴ and R^(4′) may be the same ordifferent and each independently represents a hydrogen atom or an alkylgroup containing from 1 to 6 carbon atoms. Among the above, specificexamples of R² include NHSO₂CH₃, NHSO₂C₂H₅, NHSO₂C₆H₅, NHSO₂CH₂C₆H₅,SO₂NHCH₃, SO₂NHC₂Hs, NHSO₂N(CH₃)₂ and NHSO₂N(C₂H₅)₂. Particularlypreferred examples include NHSO₂CH₃, SO₂NHCH₃ and NHSO₂N(CH₃)₂.

Within the combinations of R¹ and R², the combination in which R¹ is ahydrogen, fluorine, chlorine or bromine atom at para-position(2-position) and R² is NHSO₂CH₃ or NHSO₂N(CH₃)₂ is preferred. Thecombination in which R¹ is a hydroxyl group at para-position(2-position) and R² is SO₂NHCH₃ is also preferred.

R⁵ and R⁵¹ are a hydrogen atom or a (C₁-C₆)alkyl group. Examples thereofinclude a hydrogen atom, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neopentyl andn-hexyl, with a hydrogen atom, methyl or ethyl being preferred.

All of Z¹ to Z⁶ represent a carbon atom; or one of them represents anitrogen atom and the others represent a carbon atom. For example, themeanings of Z¹ to Z⁶ include the case in which all of them represent acarbon atom, the case in which Z¹ represents a nitrogen atom and Z² toZ⁶ represent a carbon atom, the case in which Z² represents a nitrogenatom and Z¹ and Z³ to Z⁶ represent a carbon atom, and the case in whichZ³ represents a nitrogen atom and Z¹, Z² and Z⁴ to Z⁶ represent a carbonatom. Preferred examples of the meanings of Z¹ to Z⁶ include the case inwhich all of them represent a carbon atom, the case in which Z¹represents a nitrogen atom and Z² to Z⁶ represent a carbon atom, and thecase in which Z² represents a nitrogen atom and Z¹ and Z³ to Z⁶represent a carbon atom.

R⁶ and R⁷ may be the same or different and each independently representsa hydrogen atom, a (C₁-C₆)alkyl group, a (C₁-C₆)alkyl group optionallysubstituted with one or more halogen atoms, an optionally substituted—(CH₂)_(n)-phenyl group, —CH═CH—CO₂R⁵ or —(CH₂)_(n)—R⁸. R⁸ representsOR⁵, CN, NR⁴¹R^(41′), CO₂R⁵, SO₃R⁵, SO₂(C₁-C₆)alkyl, SO₂NR⁴¹R^(41′),C(═O)R⁵, C(═O)NR⁴¹R^(41′)or NR⁵¹COR⁵, wherein R⁵ and R⁵¹ are as definedabove and wherein R⁴¹ and R^(41′) may be the same or different and eachindependently represents a hydrogen atom, a (C₁-C₆)alkyl group or a(C₃-C₆)cycloalkyl group, or R⁴¹ and R^(41′) taken together represent a(C₂-C₆)alkylene group; or R⁸ is a heterocycle selected from pyridyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,1,2,4-oxadiazolyl, isoxazolyl, tetrazolyl, pyrazolyl,hexamethyleneiminyl, piperidinyl and pyrrolidinyl, wherein one of thering nitrogen atoms of imidazolyl, triazolyl and tetrazolyl may beoptionally substituted with a (C₁-C₆)alkyl group which is optionallysubstituted with one or more halogen atoms; wherein with respect to oneor more of the ring carbon atoms of the each heterocycle, each of themmay be optionally substituted with one or more substituents which areindependently selected from hydrogen, a (C₁-C₆)alkyl group optionallysubstituted with one or more halogen atoms, a halogen atom, nitro, cyanoand —(CH₂)_(n)—R⁹; and wherein the ring nitrogen atom ofhexamethyleneiminyl, piperidinyl and pyrrolidinyl may be substitutedwith a (C₁-C₆)alkyl group, a (C₃-C₆)cycloalkyl group, COR⁵, COOR⁵,CONR⁴R^(4′) or SO₂R⁵. R⁹ represents NR⁴R^(4′), CO₂R⁵, C(═O)—NR⁴R^(4′),OR⁵, SO₃R⁵, SO₂(C₁-C₆)alkyl or SO₂NR⁴R^(4′), wherein R⁵, R⁴ and R^(4′)are as defined above.

R⁶ and R⁷ are as defined above, provided that the combinations of R⁶ andR⁷ are excluded in which they are each independently selected from ahydrogen atom, an alkyl group containing from 1 to 6 carbon atoms and anoptionally substituted —(CH₂)_(n)-phenyl group wherein n=0 or 1. Withrespect to the combinations of R⁶ and R⁷, preference is given to thecombination in which R⁶ is any one of 3-pyridyl, 4-pyridyl,3-piperidinyl, N-t-butyloxycarbonyl-3-piperidinyl,2-ethoxycarbonylethyl, 2-(N,N-dimethylaminocarbonyl)ethyl and2-acetylaminoethyl and R⁷ is methyl or ethyl when all of Z¹ to Z⁶represent a carbon atom. Particularly preferably, R⁷ is methyl. Further,when Z² is a nitrogen atom and Z¹ and Z³ to Z⁶ represent a carbon atom,R⁶ may be absent and R⁷ may be methyl, ethyl, methoxy or the like, withmethyl being preferred.

The “substituent” which may exist on the “optionally substituted—(CH₂)_(n)-phenyl group” is a hydroxyl group, a halogen atom, atrifluoromethyl group, a (C₁-C₆)alkyl group, a (C₁-C₆)alkoxy group, a(C₁-C₆)acyl group, NR⁴R^(4′), NHCO(C₁-C₆)alkyl, NHCH₂C₆H₅,NHSO₂(C₁-C₆)alkyl, NHSO₂CH₂C₆H₅, a nitro group or a cyano group. Thenumber of the substituents on the phenyl group is from 1 to 5, andpreferably from 1 to 2. Although the position of substitution is notparticularly limited, the position is preferably meta-position withrespect to (CH₂)_(n). Preferred examples of the substituent include amethoxy group and a hydroxyl group.

Further, R⁴ and R^(4′) contained in R³, R⁹ and the substituent on theoptionally substituted —(CH₂)_(n)-phenyl group are as defined above andmay be the same or different. Likewise, R⁵ contained in R³, R⁸ and R⁹ isas defined above and may be the same or different.

When R⁶ and/or R⁷ is imidazolyl, triazolyl or tetrazolyl, one or morering carbon atoms of the each heterocyclic ring may be independentlyoptionally substituted with one or more substituents which areindependently selected from a hydrogen atom, a (C₁-C₆)alkyl groupoptionally substituted with one or more halogen atoms, a halogen atom,nitro, cyano and —(CH₂)_(n)—R⁹ wherein R⁹ is as defined above. In thisconnection, the aforementioned term “one or more substituents” means“from 1 to a” substituents when a is defined as the number of allpositions on which a substituent can exist (i.e. the number ofsubstituents when wholly substituted). Although the position of eachsubstituent and the combination of substituents are not limited,preference is given to the case in which there is no substituent (i.e.all of the substituents being a hydrogen atom) or to the case in whichthere are two or more substituents and one of them is a halogen atom ora methyl group and the others are hydrogen atoms.

X represents an oxygen atom, a sulfur atom or NR¹⁰ wherein R¹⁰represents a hydrogen atom, an optionally substituted —(CH₂)_(n)-phenylgroup, a —(C₁-C₁₀)alkyl group or a —(CH₂)_(n)—R⁸ wherein R⁸ is asdefined above, with NH, an oxygen atom or a sulfur atom being preferred.Further, X is more preferably NH. The abovementioned n is an integer offrom 0 to 6, and preferably of from 0 to 3.

Y represents an oxygen atom, NH, a sulfur atom or a methylene group,with an oxygen atom, NH or a sulfur atom being preferred. Further, Y ismore preferably an oxygen atom or NH.

In the general formula (I) set forth above, *1 is an asymmetric carbonatom, and *2 is also an asymmetric carbon atom when R⁵ is a (C₁-C₆)alkylgroup. In such a case, the compound of the general formula (I) can be inthe form of four isomers, that is to say (R,R), (R,S), (S,S) and (S,R)which are each described in order of *1 and *2. When R⁵ is a hydrogenatom, two isomers can exist. Not only optically pure isomers, but alsomixtures of the two isomers with any mixing ratio are encompassed in thepresent invention. Further, mixtures of optional three isomers and themixture of all the four isomers are also encompassed in the presentinvention. From the viewpoint of the expression of pharmacologicalactivity, a preferred configuration of the asymmetric carbon *1 is theconfiguration R.

In addition, illustrative examples of specific compounds of the presentinvention represented by the general formula (I) wherein Z¹ represents acarbon atom or a nitrogen atom and Z² to Z⁶ represent a carbon atom,include:

-   -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylic        acid;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylic        acid;    -   (R)-N-[3-[2-[2-(3-hydroxymethyl-2-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(N′,N′-dimethylamino)methyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylate;    -   (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylic        acid;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionate;    -   (R)-3-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionic        acid;    -   (R)-N-[3-[2-[2-[3-(2-aminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(2-N′,N′-dimethylamino)ethyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-acetyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methane        sulfonamide;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;    -   (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   (R)-[6-[2-[2-(4-hydroxy-3-methylsulfamoyl)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetic        acid;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]acetic        acid;    -   (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]propionic        acid;    -   (R)-N-[3-[2-[2-[2-(2-methoxyethyl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-ethyl-2-(2-methoxyethyl)-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylic        acid;    -   ethyl        (R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;    -   ethyl        (R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;    -   ethyl        (R,R)-6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]propoxy]-3-methyl-i        1H-indole-2-carboxylate;    -   ethyl        (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylate;    -   (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetate;    -   (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetic        acid;    -   ethyl        (R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]acetate;    -   ethyl        (R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]propionate;    -   (R)-N-[3-[2-[2-(2-pyrrolidylcarbonylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[2-(isoxazol-3-yl)benzofuran-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-5-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;    -   (R)-1-benzyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-1-[3-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-1-[4-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylic        acid;    -   (R)-N-[3-[2-[2-(2,3-ditrifluoromethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(3-ethyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-4-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[2-(N′-t-butyloxycarbonylpiperidin-3-yl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[1-hydroxy-2-(3-methyl-2-piperidin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-[3-(2-acetylaminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-3-[6-[2-[2-hydroxy-2-(3-methylsulfonylaminophenyl)ethylamino]ethoxy]-3-phenyl-1H-indol-2-yl]propionate;    -   (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;    -   ethyl        (R)-3-[6-[2-[2-(4-fluoro-3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]propionate;    -   (R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethyl]amino]ethoxy]-1H-indol-2-yl]-N,N-dimethylpropionamide;    -   ethyl        (R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]propionate;        and    -   ethyl        (R)-2-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]acetate.

Further, illustrative examples of specific compounds of the presentinvention represented by the general formula (I) wherein Z² represents anitrogen atom and Z¹ and Z³ to Z⁶ represent a carbon atom, include:

-   -   (R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[3-[2-[2-(3-methoxyindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;    -   (R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;    -   (R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;    -   (R)—N-methyl-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamide;        and    -   (R,R)-N-[3-[1-hydroxy-2-[1-methyl-2-(3-methylindazol-6-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide.

Processes for the preparation of compounds represented by the generalformula (I) are illustrated in the following.

[Preparation Process 1]

Compounds of the general formula (I) may be prepared according to theprocesses described in WO 97/25311 and WO 00/58287. That is, anobjective compound of the general formula (I) may be prepared by, as thefirst step, reacting a compound represented by the general formula (II):

wherein W represents a hydrogen atom or an amino-protecting group, andR⁵, R⁶, R⁷, X, Y, Z¹ to Z⁶ and *2 are each as defined above, with acompound represented by the general formula (III):

wherein R^(1′)represents a hydrogen atom, OA¹ (wherein A¹ represents ahydroxyl-protecting group) or a halogen atom, R^(2′) represents NW²SO₂R³or SO₂NR⁴R^(4′), W² represents a hydrogen atom or an amino-protectinggroup, L² represents a leaving group, and R³, R⁴ and R^(4′) are each asdefined above, to give an amino ketone (—CO—CH₂—NW—); as the secondstep, reducing the thus obtained amino ketone compound to give an aminoalcohol (—CHOH—CH₂—NW—) compound; and, as the final step, optionallyremoving the hydroxyl-protecting group A¹ on the benzene ring and, whenW and W² are not hydrogen atoms but amino-protecting groups, removingthem. Examples of L² include a chlorine atom, a bromine atom, an iodineatom and the like. When W and W2 represent an amino-protecting group,the amino-protecting group is not limited as long as it is a protectinggroup used in a common organic synthesis. Preferred examples of theamino-protecting group include a benzyl group, a substituted benzylgroup and the like. When R¹ is OA¹, the hydroxyl-protecting group A¹ isalso not limited as long as it is a protecting group used in a commonorganic synthesis. Preferred examples of the hydroxyl-protecting groupinclude a benzyl group, a substituted benzyl group and the like.

The amount of the compound represented by the general formula (II) to beused in the first step is from 1 to 5 mol for 1 mol of the compoundrepresented by the general formula (III). A base may be added toneutralize an acid generated by the reaction. Examples of the base to beused include organic bases such as triethylamine, diisopropylethylamineand pyridine, inorganic bases such as potassium carbonate, sodiumhydrogencarbonate and sodium hydroxide and the like. Further, compoundsof the general formula (II) may be used also in the form of their salts,provided that the abovementioned base is added.

Examples of the solvent to be used in the reaction include loweralcohols such as methanol, ethanol and isopropyl alcohol, chlorinatedhydrocarbons such as methylene chloride, chloroform and1,2-dichloroethane, tetrahydrofuran, dimethylformamide,dimethylsulfoxide and the like, with dimethylformamide being preferred.Although reaction temperature and reaction time are not limited, thereaction is carried out at a temperature of from −30° C. to the boilingpoint of the selected solvent, preferably a temperature of from 0° C. to30° C., for 10 minutes to 24 hours.

The amino ketone generated in the first step may be used in thereductive reaction of the second step without isolation from thereaction mixture. However, the amino ketone may be optionally extractedand purified before the reductive reaction. Examples of the reducingagent to be used include sodium borohydride, sodium cyanoborohydride,borane and the like. Examples of the solvent to be used in the reactioninclude lower alcohols such as methanol, ethanol and isopropyl alcohol,tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, withethanol and dimethylformamide being preferred. Although reactiontemperature and reaction time are not limited, the reaction is carriedout at a temperature of from −30° C. to the boiling point of theselected solvent, preferably a temperature of from 0° C. to 30° C., for10 minutes to 24 hours.

When the removal of the amino-protecting group and/orhydroxyl-protecting group is needed as the final step, they may beremoved under reaction conditions usually used for removing theprotecting groups to be used. When a benzyl or substituted benzyl groupis used as the protecting group, it may be removed, for example, by ahydrogenation reaction using palladium/activated carbon as a catalyst.

Compounds represented by the general formula (I), which containasymmetric carbons represented by *1 and *2, are obtained as a racemicmixture by the process set forth above. The racemic mixture can beoptically resolved into optically active substances by converting theracemic mixture to acid addition salts with an optically active acidsuch as camphorsulfonic acid or mandelic acid followed by a fractionalcrystallization treatment. The racemic mixture may be also opticallyresolved using a commercially available optically active column.

Further, optically active substances may be also obtained by carryingout an asymmetric reduction treatment with a hydrogen donating compoundin the presence of an asymmetric reduction catalyst in the second stepaccording to the process described in WO 00/58287.

[Preparation Process 2]

Compounds of the general formula (I) may be also prepared by anotherprocess set forth below according to the processes described in WO97/25311 and WO 01/04092. That is, an objective compound of the generalformula (I) may be prepared by, as the first step, reacting a compoundrepresented by the general formula (II) with a compound represented bythe general formula (IV):

wherein L² represents a leaving group, A represents ahydroxyl-protecting group, and R^(1′), R^(2′) and *1 are as definedabove, to give an amino ether (—CHOA ²—CH₂—NHW—) compound; and, as thesecond step, removing the hydroxyl-protecting group A², optionallyremoving the hydroxyl-protecting group A¹, and when W and W² are nothydrogen atoms but amino-protecting groups, removing them. Examples ofthe leaving group L² include a chlorine atom, a bromine atom, an iodineatom and the like, with iodine atom being preferred. W and W² are as setforth above in Preparation Process 1. The hydroxyl-protecting group A¹when R^(1′) is OA¹ is also as set forth above in Preparation Process 1.Another hydroxyl-protecting group A² is also not limited as long as itis a protecting group used in a common organic synthesis. Preferredexamples of the hydroxyl-protecting group include a triethylsilyl group.

The amount of the compound represented by the general formula (II) to beused is from 1 to 1.5 mol for 1 mol of the compound represented by thegeneral formula (IV). A base may be added to neutralize an acidgenerated by the reaction. Examples of the base to be used includetriethylamine, diisopropylethylamine and the like. Further, compounds ofthe general formula (II) may be used also in the form of their salts,provided that the abovementioned base is added.

Examples of the solvent to be used in the reaction includedimethylformamide, dimethylacetamide, dimethylsulfoxide and the like,with dimethylformamide being preferred. Although reaction temperatureand reaction time are not limited, the reaction is carried out at atemperature of from 0° C. to 90° C., preferably a temperature of 60° C.,for 10 minutes to 24 hours. The hydroxyl-protecting group A² andoptionally the other protecting groups may be removed under reactionconditions usually used for removing the protecting groups to be used. Atriethylsilyl group as A² may be removed using, for example,tetrabutylammonium fluoride.

Optically active substances may be prepared as set forth above inPreparation Process 1 by formation of acid addition salts with anoptically active acid followed by a fractional crystallizationtreatment, or optical resolution using a commercially availableoptically active column or the like.

Further, an optically active compound represented by the general formula(I) may be also prepared using an optically active compound representedby the general formula (IV) prepared according to the processesdescribed in, for example, WO 97/25311 and WO 01/04092, and an compoundrepresented by the general formula (II) wherein R⁵ is a hydrogen atom.

[Preparation Process 3]

Compounds of the general formula (I) may be also prepared by anotherprocess set forth below according to the process described in WO01/04092. That is, an objective compound of the general formula (I) maybe prepared by reacting a compound represented by the general formula(V):

wherein L³ represents a hydroxyl group or a leaving group, and R^(1′),R²′, R⁵, A², W, *1 and *2 are as defined above, with a compoundrepresented by the general formula (VI):

wherein Y represents an oxygen atom or a sulfur atom, and R⁶, R⁷, X andZ¹ to Z⁶ are as 2 defined above; and, as the second step, removing thehydroxyl-protecting group A², optionally removing thehydroxyl-protecting group A¹, and when W and W² are not hydrogen atomsbut amino-protecting groups, removing them.

Examples of the leaving group L³ include a chlorine atom, a bromineatom, an iodine atom and the like, with bromine atom being preferred.

Compounds represented by the general formula (III) are known compoundsand may be prepared by the process described in, for example, WO97/25311 or the literature (J. Med. Chem., vol. 10, p. 462 (1966)).Further, compounds represented by the general formula (IV) are knowncompounds and may be prepared by the process described in, for example,WO 97/25311. Further, compounds represented by the general formula (V)are known compounds and may be prepared by the process described in, forexample, WO 01/04092.

Compounds represented by the general formula (II) are characteristic asimportant intermediates for synthesizing compounds represented by thegeneral formula (I) and are novel compounds except that R⁵ represents a(C₁-C₆)alkyl group and both of R⁶ and R⁷ represent a hydrogen atom.Processes for the preparation of compounds represented by the generalformula (II) are illustrated in the following.

[Preparation Process a]

Compounds represented by the general formula (II) wherein Y is an oxygenatom may be prepared by the process set forth below. That is, anobjective compound may be obtained by reacting a compound represented bythe general formula (VI):

wherein Y represents an oxygen atom, and R⁶, R⁷, X and Z¹ to Z⁶ are asdefined above, with a compound represented by the general formula (VII):

wherein L¹ represents a leaving group, W¹ represents an amino-protectinggroup, and R⁵ and *2 are as defined above, in the presence of a base; asthe second step, removing the amino-protecting group W¹; and, as thefinal step, optionally re-protecting this amino group with anotherprotecting group W. Even if W is a hydrogen atom (i.e. the amino groupis in the free form), the compound may be used in the followingreaction. Examples of the leaving group L¹ include a chlorine atom, abromine atom, an iodine atom and the like. The amino-protecting group W¹is not limited as long as it is a protecting group used in a commonorganic synthesis. Preferred examples include a benzyloxycarbonyl group,a substituted benzyloxycarbonyl group, a tert-butoxycarbonyl group andthe like. W may be selected as set forth above in Preparation Process 1for compounds of the formula (I).

The amount of the compound represented by the general formula (VII) tobe used in the first step is from 1 to 5 mol for 1 mol of the compoundrepresented by the general formula (VI). Examples of the base to be usedinclude potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, sodium hydride, sodium methoxide, triethylamine andthe like. Examples of the solvent to be used in the reaction includetetrahydrofuran, dimethylformamide, dimethylacetamide,dimethylsulfoxide, acetonitrile and the like. Although reactiontemperature and reaction time are not limited, the reaction is carriedout at a temperature of from 0° C. to the boiling point of the selectedsolvent, preferably a temperature of from room temperature to 90° C.,for 10 minutes to 24 hours.

In the second step, the amino-protecting group W¹ may be removed underreaction conditions usually used for removing the protecting group to beused. When a benzyloxycarbonyl or substituted benzyloxycarbonyl group isused as the protecting group, it may be removed, for example, by ahydrogenation reaction using palladium/activated carbon as a catalyst.When a tert-butoxycarbonyl group is used as the protecting group, it maybe removed using an acid such as trifluoroacetic acid or hydrochloricacid.

[Preparation Process b]

Compounds represented by the general formula (II) wherein Y is a sulfuratom may be prepared by the process set forth below. That is, anobjective compound may be obtained by reacting a compound represented bythe general formula (VI):

wherein Y represents a sulfur atom, and R⁶, R⁷, X and Z¹ to Z⁶ are asdefined above, with a hydrochloride or hydrobromide salt of a compoundrepresented by the general formula (VII):

wherein W¹ represents a hydrogen atom, L¹ represents a chlorine atom ora bromine atom, and R⁵ and *2 are as defined above.

The amount of the compound represented by the general formula (VII) tobe used is from 1 to 1.5 mol for 1 mol of the compound represented bythe general formula (VI). The reaction is usually carried out in thepresence of a base. Examples of the base include organic bases such astriethylamine, diisopropylethylamine and pyridine, inorganic bases suchas potassium carbonate, sodium hydrogencarbonate and sodium hydroxideand the like. Examples of the solvent to be used in the reaction includelower alcohols such as methanol, ethanol and isopropyl alcohol, aceticacid, chlorinated hydrocarbons such as methylene chloride, chloroformand 1,2-dichloroethane, tetrahydrofuran, dimethylformamide,dimethylsulfoxide and the like, which may be used alone or as a mixedsolvent comprising plural solvents. Preferably, a mixed solvent oftetrahydrofuran and methanol is used. Although reaction temperature andreaction time are not limited, the reaction is carried out at atemperature of from −30° C. to the boiling point of the selectedsolvent, preferably a temperature of from 0° C. to 30° C., for 10minutes to 24 hours.

[Preparation Process c]

Compounds represented by the general formula (II) wherein Y is NH may beprepared by the process set forth below. That is, as the first step, atriflate compound represented by the general formula (VIII):

wherein R⁶, R⁷, X and Z¹ to Z⁶ are as defined above, is reacted with acompound represented by the general formula (IX):

wherein W¹ and W³ each represent an amino-protecting group, and R⁵ and*2 are as defined above. This reaction can be carried out according tothe process described in the literature (B. H. Yang et al., Journal ofOrganometallic Chemistry, 576, pp. 125-146, 1999).

And then, a compound represented by the general formula (II′):

wherein R⁵, R⁶, R⁷, X, Z¹ to Z⁶, W and W³ are as defined above, may beobtained by, as the second step, removing the amino-protecting group W¹,and, as the final step, optionally re-protecting this amino group withanother protecting group W.

The triflate compound of the general formula (VIII) may be obtained byapplying reaction conditions commonly used for converting a hydroxylgroup into a triflate group to a compound of the general formula (VI)wherein Y is an oxygen atom. The amino-protecting group W¹ is notlimited as long as it is a protecting group used in a common organicsynthesis. Preferred examples include a benzyloxycarbonyl group, asubstituted benzyloxycarbonyl group, a tert-butoxycarbonyl group and thelike. The amino-protecting group W³ is not limited as long as it is aprotecting group used in a common organic synthesis. Preferred examplesinclude a benzyl group, a substituted benzyl group and the like. Thecompound having the amino-protecting group W³ is more preferablyprovided for the next reaction in the protected form without removingthe amino-protecting group W³ than in the form of free amine obtained byremoving the amino-protecting group W³. The compound in which W is ahydrogen atom (i.e. the amino group being in the free form) can be alsoprovided for the next reaction. W may be selected as set forth above inPreparation Process 1 for compounds of the general formula (I). In thesecond step, the amino-protecting group W¹ may be removed under reactionconditions usually used for removing the protecting group to be used.

[Preparation Process d]

Compounds represented by the general formula (II) wherein Y is amethylene group may be prepared by or according to the known processdescribed in the literature (Troxler et al., Helv. Chim. Acta., vol. 51,p. 1616, 1968) or WO 94/29290. Further, other compounds represented bythe general formula (II) wherein Y is a methylene group may be alsoprepared according to the known process for preparing indolederivatives, the known process for preparing benzofuran derivatives orthe known process for preparing benzothiophene derivatives.

Then, compounds represented by the general formula (VI):

wherein Y represents an oxygen atom or a sulfur atom, and R⁶, R⁷, X andZ¹ to Z⁶ are as defined above, may be prepared by or according to theknown processes set forth below.[Preparation Process i]

Namely, compounds represented by the general formula (VI) set forthabove wherein R⁷ represents a hydrogen atom or a (C₁-C₆)alkyl groupoptionally substituted with one or more halogen atoms may be synthesizedaccording to the process described in WO 94/29290.

[Preparation Process ii]

Then, compounds represented by the general formula (VI) wherein Yrepresents an oxygen atom and Z¹ to Z⁶ represents a carbon atom may besynthesized by the process indicated in the following reaction scheme.

Namely, a compound represented by the general formula (X):

wherein Z¹ to Z⁶ represent a carbon atom, R⁷ represents a hydrogen atom,Y represents an oxygen atom, A¹ represents a hydroxyl-protecting group,and X and R⁶ are as defined above, is formylated via a Vilsmeyerreaction to give a compound represented by the general formula (XI):

wherein R⁶, X, Y, Z¹ to Z⁶ and A¹ are each as defined above; then, R⁷ isintroduced by subjecting the resulting formyl group to a reactioncommonly used in organic chemical reactions, to give a compoundrepresented by the general formula (XII):

wherein R⁶, R⁷, X, Y, Z¹ to Z⁶ and A¹ are each as defined above.Finally, a compound represented by the general formula (VI) may beobtained by removing the protecting group A¹ under a commonly usedcondition.

A compound represented by the general formula (X) may be commerciallyavailable, or may be synthesized by the process described in WO 94/29290or according to the processes described in the following literatures.

That is, a compound represented by the general formula (X) wherein X═NH,Y═O, Z¹ represents a nitrogen atom or a carbon atom, Z² to Z⁶ representa carbon atom and R⁶═an alkyl group or an aryl group may be synthesizedby the process described in the literature (Mentzer et al., Bull. Soc.Chim. Fr., p. 555, p. 559, 1950) or the literature (E. von Angerer etal., J. Med. Chem., vol. 27, No. 25, pp. 1439-1447, 1984). Likewise, acompound represented by the general formula (X) wherein X═O, Y═O,Z¹represents a nitrogen atom or a carbon atom, Z² to Z⁶ represent acarbon atom and R⁶=an alkyl group may be synthesized by the processdescribed in the literature (G. Pandey et al., Tetrahedron Lett., vol.30, No. 14. pp. 1867-1870, 1989). A compound represented by the generalformula (X) wherein, X═S, Y═O, Z¹ represents a nitrogen atom or a carbonatom, Z² to Z⁶ represent a carbon atom and R⁶=an aryl group may besynthesized by the process described in the literature (Fries et al.,Justus Liebigs Ann. Chem., vol. 527, p. 83-114, 1937) or the literature(E. von Angerer et al., J. Steroid Biochem. Mol. Biol., vol. 41, pp.557-562). A compound represented by the general formula (X) whereinX═NH, Y═O, Z² represents a nitrogen atom, Z¹ and Z³ to Z⁶ represent acarbon atom and R⁷=an alkyl group may be synthesized by the processdescribed in the literature (S. Caron et al., Synthesis, No. 4, pp.588-592, 1999) or the literature (Davies et al., J. Chem. Soc., pp.2412-2419, 1955). A compound represented by the general formula (X)wherein X═NH, Y═NH, Z² represents a nitrogen atom, Z¹ and Z³ to Z⁶represent a carbon atom and R⁷═an alkyl group may be synthesized by theprocess described in the literature (Davies et al., J. Chem. Soc., pp.2412-2419, 1955).

In addition, a compound represented by the general formula (XI) may besynthesized by the process described in the literature (R. Gastpar etal., J. Med. Chem., vol. 41, No. 25, pp. 4965-4972, 1998) or theliterature (K. Cardwell et al., J. Am. Chem. Soc., vol. 110, pp.2242-2248, 1988).

The present compounds and the starting compounds and intermediates forpreparing each of the present compounds which can be obtained as setforth above may be isolated and purified by the conventional means suchas extraction, crystallization, distillation, chromatography,recrystallization or the like.

Salts of a compound of the general formula (I) according to the presentinvention may be a known salt, and examples thereof includehydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, citrate, maleate, tartrate, fumarate, gluconate,methanesulfonate and the like, and acid addition salts with an opticallyactive acid such as camphorsulfonic acid, mandelic acid or substitutedmandelic acid. Among them, pharmaceutically acceptable salts areparticularly preferred.

When a compound of the general formula (I) is converted into its salt,an acid addition salt of the compound can be obtained by dissolving thecompound in alcohol such as methanol or ethanol, to which the equivalentamount to several times amount of the acid component is then added. Theacid component to be used may be a pharmaceutically acceptable mineralor organic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogensulfate, dihydrogen phosphate, citric acid, maleic acid,tartaric acid, fumaric acid, gluconic acid or methanesulfonic acid.

Compounds of the present invention and pharmaceutically acceptable saltsthereof, which have no recognizable toxic effect, are useful as amedicine. For example, the compounds, which have β3-receptor agonistactivities, can be used as a medicine for treating and preventingβ3-receptor associated diseases. The term “β3-receptor associateddisease” is a generic term directed to diseases which can be improved byagonistic effects mediated by the receptor. Examples of β3-receptorassociated diseases include diabetes, obesity, hyperlipidemia, fattyliver, digestive diseases (preferably dyskinesia of digestive system orulcer) and depression. In addition, the compound can be used as amedicine for treating and preventing fatty liver, urinary incontinenceand others.

Urinary incontinence is defined by International Incontinence Society asa condition in which involuntary urine loss is a social or hygienicproblem and is objectively demonstrable.

Compounds of the present invention are safe compounds with a low acutetoxicity. Further, compounds of the present invention are characterized,for example, in that they do not inhibit some of drug metabolizingenzymes (cytochrome P-450). Methods for determining whether cytochromeP-450 may be inhibited or not include known methods described, forexample, in the literature (Crespi C. L. et al., AnalyticalBiochemistry, vol. 248, pp. 188-190, 1997).

Even compounds of the present invention and pharmaceutically acceptablesalts thereof obtained by a synthetic means have β3-receptor agonisticeffects, and those generated as a result of an in vivo metabolism alsohave the same β3-receptor agonistic effects. Therefore, compounds whichgenerate the present compound as a result of an in vivo metabolism arealso useful as a medicine.

A medicine of the present invention is preferably prepared in the formof a pharmaceutical composition by optionally adding a pharmaceuticallyacceptable carrier to an effective amount of a compound represented bythe general formula (I) or a salt thereof. Examples of pharmaceuticallyacceptable carriers include excipients, binders such ascarboxymethylcellulose, disintegrators, lubricants, auxiliaries and thelike.

When a compound of the present invention is administered to humans, itcan be orally administered in the form of tablet, powder, granule,capsule, sugar-coated tablet, solution, syrup or the like. Further, itcan be parenterally administered in the form of injection or the like.Although the dosage will vary dependent on the age and weight of thepatient and the extent of disease, the daily dosage for an adult isusually from 0.01 to 2000 mg, which is singly administered or is dividedinto several dosages and then administered. The duration ofadministration can vary between several weeks and several months and theeveryday medication is usually applied. However, the daily dosage andduration of administration can be increased or decreased from the aboveranges dependent on the conditions of patient.

The disclosures in the text of specification of Japanese PatentApplication No. 2001-327467, from which the present application claimsthe priority right, are incorporated herein.

DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The following Examples, Reference Examples and Test Examplesspecifically illustrate this invention but are not intended to limit itin any way.

In the following examples, each analysis was carried out as follows.

(1) Fast Atom Bombardment Mass Spectrum (FAB-MS)

Fast atom bombardment mass spectrum was determined with a JMS-AX500 typemass spectrometer manufactured by JEOL. LTD or a JMS-SX102 type massspectrometer manufactured by JEOL. LTD. The matrix used was3-nitrobenzyl alcohol.

(2) Liquid Chromatography-Mass Spectrometry (LC-MS)

The mass spectrometer used was a Platform-LC type mass spectrometermanufactured by Micromassm (England). A compound to be analyzed wasionized by erectrospray (ESI) method. The liquid chromatograph used wasthat manufactured by GILSON (France). The separation column used wasMightysil RP-18 GP 50-4.6 (product number 25468-96) manufactured byKANTO KAGAKU (Japan). The eluting conditions are as follows.

Flow rate: 2 mL/min;

Solvent:

-   -   Liquid A=water containing 0.1%(v/v) acetic acid;    -   Liquid B=acetonitrile containing 0.1%(v/v) acetic acid;    -   A linear gradient of 5-100%(v/v) Liquid B over 5 minutes (from 0        to 5 min) was used.

Elution time was indicated by “minute”.

(3) Proton Nuclear Magnetic Resonance (¹H-NMR) Spectrum

The determination of proton nuclear magnetic resonance spectrum wascarried out using a Gemini-300 type nuclear magnetic resonance apparatusmanufactured by Varian (U.S.A.). Tetramethylsilane was used as theinternal standard and chemical shift was indicated in 6 (ppm). In thisconnection, the splitting patterns were indicated using the followingabbreviations. s: singlet; d: doublet; t: triplet; q: quartet; quintet:quintet; m: multiplet; dd: double doublet; dt: double triplet; brs:broad singlet.

(4) Thin Layer Chromatography (TLC)

The thin layer chromatography (TLC) used was TLC plate (silica gel 60F₂₅₄, product number 1,05715) manufactured by Merck (Germany). Thedetection of a compound was carried out by developing the plate followedby irradiation with UV (254 nm).

(5) Purification Chromatography

A purifying process with silica gel column was carried out using silicagel 60 manufactured by Merck (Germany). An objective compound was elutedwith a mixed solvent (n-hexane/ethyl acetate or chloroform/methanol).

A purifying process with reversed phase column was carried out using aYMC CombiPrep ODS-A CCAAS05-0520WT type column manufactured by YMC(Japan). An objective compound was eluted by gradient elution usingwater/acetonitrile (containing 0.1%(v/v) acetic acid). The detailedeluting conditions are as follows.

Flow rate: 20 mL/min;

Solvent:

-   -   Liquid A=water containing 0.1%(v/v) trifluoroacetic acid;    -   Liquid B=acetonitrile containing 0.1%(v/v) trifluoroacetic acid;    -   From 0 to 1 min: Liquid B was maintained at 5%(v/v).    -   From 1 to 11 min: A linear gradient of 5-50%(v/v) Liquid B was        used.    -   From 11 to 16 min: A linear gradient of 50-100%(v/v) Liquid B        was used.

The following abbreviations are used in Examples set forth below.

-   -   DMSO: dimethylsulfoxide    -   THF: tetrahydrofuran    -   DMF: dimethylformamide

With respect to intermediates about which no preparing process andreference are described in Examples or Reference Examples, theirchemical names and the literatures comprising described thereinprocesses for preparing them are mentioned below.

N-(3-bromoacetylphenyl)methanesulfonamide (Larsen et al., J. Med. Chem.,vol. 9, pp. 88-97, 1966);

-   -   2-benzyloxy-5-bromoacetyl-N-methylbenzenesulfonamide        (JP-A-9-249623);    -   N-(5-bromoacetyl-2-chlorophenyl)methanesulfonamide        (JP-A-9-249623); and    -   N-(3-bromoacetyl-4-fluorophenyl)methanesulfonamide (WO        91/12236).

Reference Example 1

Synthesis of(R)-[3-[2-[N-benzyl-N-(2-hydroxyethyl)amino]-1-triethylsilyloxy]ethyl]phenyl](methylsulfonyl)benzylamine

In accordance with the process described in Example 26 of WO 01/04092,the title compound (15.1 g) was obtained from N-benzylethanolamine (31.4mL) and Compound 10 (17.6 g) which had been obtained according to theprocess described in Example 29 of the same patent publication.

¹H-NMR (CDCl₃): δ(ppm) 0.36-0.45 (6H, m), 0.79 (9H, t, J=7.8), 1.50-1.80(1H, brs), 2.49-2.69 (3H, m), 2.71-2.80 (1H, m), 2.93 (3H, s), 3.37 (2H,t, J=5.4), 3.59 (1H, d, J=13.8), 3.66 (1H, d, J=13.8), 4.49 (1H, t,J=6.3), 4.80 (1H, d, J=14.4), 4.90 (1H, d, J=14.4), 7.11-7.35 (14H, m).

Reference Example 2

Synthesis of N-(3-acetyl-4-chlorophenyl)methanesulfonamide

1-(5-Amino-2-chlorophenyl)ethanone (411 mg; synthesized by the processreported by Radziejewski et al., Heterocycles, vol. 26, pp. 1227-1238,1987) was dissolved in toluene (5 mL), and pyridine(235 μL) andmethanesulfonyl chloride (225 μL) were added. The resulting mixture wasstirred at room temperature for 50 minutes. After adding water (50 mL),the reaction mixture was extracted with ethyl acetate (50 mL). Theorganic layer was washed with an aqueous 1 N hydrochloric acid solution(50 mL) and saturated brine (50 mL) and then dried over anhydrous sodiumsulfate (5 g). The solvent was distilled off under reduced pressure toyield N-(3-acetyl-4-chlorophenyl)methanesulfonamide (595 mg) as acolorless crystal.

¹H-NMR (CDCl₃): δ(ppm) 7.43-7.33 (3H, m), 7.10 (1H, brs), 3.05 (3H, s),2.67 (3H, s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.31;

LC-MS: elution time 3.1 minutes;

m/z=246(M−H)⁻.

Reference Example 3

Synthesis of N-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide

N-(3-acetyl-4-chlorophenyl)methanesulfonamide (300 mg) was dissolved indioxane (5 mL), and bromine (77 μL) was added dropwise with ice-cooling.After stirring at room temperature for 1 hour, the solvent was distilledoff under reduced pressure. The residue was washed with a water/ethanolmixture (1:1) and then dried under reduced pressure to yieldN-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide (312 mg) as acolorless crystal.

¹H-NMR (CDCl₃): δ(ppm) 7.46-7.36 (3H, m), 6.90 (1H, brs), 4.52 (2H, s),3.07 (3H, s);

TLC (4:1 n-hexane/ethyl acetate): R_(f)=0.31;

LC-MS: elution time 3.5 minutes;

m/z=324 (M−H)—.

Reference Example 4

Synthesis of N-(3-acetyl-5-aminophenyl)methanesulfonamide

3-Amino-5-nitrobenzophenone (4 g; synthesized by the process reported byBerend et al., J. Prakt. Chem., vol. 69, p. 471 (1904)) was dissolved inpyridine (40 mL), and the temperature was maintained at 50° C.Methanesulfonyl chloride (1.9 mL) was added, followed by stirring for 2hours. Additional methanesulfonyl chloride (1.7 mL) was added, followedby stirring at 50° C. for 2 hours. The reaction mixture was cooled downto room temperature and then poured into water (200 mL). The depositedprecipitate was collected by filtration and dried under reduced pressureto yield N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g) as a crudeproduct. The whole quantity of the crude product was dissolved inethanol (40 mL), and zinc dust (20 g) was added. After further addingconcentrated hydrochloric acid (2 mL), the mixture was heated to refluxfor 4 hours. The reaction mixture was filtered. To the filtrate, ethylacetate (100 mL) was added. The resulting mixture was washed with water(100 mL) three times and the organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue was purified by silica gel column chromatography (95:5chloroform/methanol) to yieldN-(3-acetyl-5-aminophenyl)methanesulfonamide (3.9 g).

¹H-NMR (DMSO-d₆); δ(ppm) 8.27 (1H, brs), 6.96 (1H, m), 6,93 (1H, m),6.71 (1H, m);

TLC (10:1 chloroform/methanol): R_(f)=0.55;

FAB-MS: m/z=229 (M+H)⁺.

Reference Example 5

Synthesis of N-(3-acetyl-5-chlorophenyl)methanesulfonamide

Sodium nitrite (0.34 g) was added in three portions to concentratedsulfuric acid (3.5 mL). After the addition was completed, the solutionwas stirred at 70° C. for 10 minutes to dissolve the sodium nitritecompletely. The resulting solution was allowed to cool down to roomtemperature and then a suspension ofN-(3-acetyl-5-aminophenyl)methanesulfonamide (1 g) in acetic acid (8 mL)was gradually added with ice-cooling. The resulting mixture was allowedto stand at room temperature for 30 minutes and then stirred at 40° C.for 30 minutes to yield a dark red diazonium salt solution. Thediazonium salt solution was gradually added to a solution of cuprouschloride (0.95 g) in concentrated hydrochloric acid (10 mL) at roomtemperature. After foaming was over, the reaction mixture was stirred at80° C. for 30 minutes and then allowed to cool down to room temperature.Water (60 mL) was added and the mixture was extracted with ethyl acetate(100 mL). The ethyl acetate layer was washed with water (100 mL) threetimes and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (98:2 chloroform/methanol) to yieldN-(3-acetyl-5-chlorophenyl)methanesulfonamide (350 mg) as a light brownpowder.

¹H-NMR (DMSO-d₆): δ(ppm) 7.72 (1H, m), 7.68 (1H, m), 7.55 (1H, m), 3.13(3H, s), 2.61 (3H,s);

TLC (10:1 chloroform/methanol): R_(f)=0.60;

FAB-MS: m/z=249 (M+H)⁺.

Reference Example 6

Synthesis of N-(3-acetyl-5-bromophenyl)methanesulfonamide

The procedure of Reference Example 4 was repeated usingN-(3-acetyl-5-aminophenyl)methanesulfonamide (1 g) as the startingmaterial except that cuprous bromide (1.5 g) and hydrobromic acid wereused instead of cuprous chloride and concentrated hydrochloric acid. Anafter-treatment according to Reference Example 4 yieldedN-(3-acetyl-5-bromophenyl)methanesulfonamide (350 mg) as a colorlesscrystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.21 (1H, brs), 7.83 (1H, m), 7,73 (1H, m),7.60 (1H, m), 3.08 (3H, s), 2.57 (3H, s);

TLC (10:1 chloroform/methanol): R_(f)=0.86;

FAB-MS: m/z=293(M+H)⁺.

Reference Example 7

Synthesis of N-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide

N-(3-acetyl-5-chlorophenyl)methanesulfonamide (500 mg) was dissolved indioxane (10 mL). The temperature was maintained at 50° C. and bromine(0.11 mL) was added. After stirring for 30 minutes, water (50 mL) wasadded to the mixture, and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with water (50 mL) twice andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure and the residue was purified by silica gelcolumn chromatography (1:2 ethyl acetate/hexane) to yieldN-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide (600 mg) as acolorless crystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.29 (1H, brs), 7.80 (1H, m), 7.70 (1H, m),7.50 (1H, m), 4.92 (2H,s), 3.80(3H,s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.85;

FAB-MS: m/z=328(M+H)⁺.

Reference Example 8

Synthesis of N-(3-bromoacetyl-5-bromophenyl)methanesulfonamide

The procedure of Reference Example 6 was repeated usingN-(3-acetyl-5-bromophenyl)methanesulfonamide (650 mg) as the startingmaterial to yield N-(3-bromoacetyl-5-bromophenyl)methanesulfonamide (510mg) as a light-brown powder.

¹H-NMR (DMSO-d₆): δ(ppm) 10.26 (1H, brs), 7.91 (1H, m), 7.75 (1H, m),7.63 (1H, m), 4.91 (2H, s), 3.09 (3H, s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.75;

FAB-MS: m/z=372(M+H).

Reference Example 9

Synthesis of 6-hydroxy-3-methyl-2-(pyridin-3-yl)-1H-indole (Step A)Synthesis of 5-methoxy-2-[(pyridin-3-yl)ethynyl]aniline

In accordance with the process described in the literature (Wang et al.,J. Org. Chem., vol. 64, pp. 925-932, 1999), the title compound (397 mg)was obtained using 2-iodo-5-methoxyaniline (519 mg; synthesizedaccording to the process described in the literature (Ma et al., J. Org.Chem., vol. 66, pp. 4525-4542, 2001)),dichlorobis(triphenylphosphine)palladium(II)(60 mg), copper iodide(I)(20mg), triethylamine (10 mL) and 3-ethynylpyridine (323 mg).

¹H-NMR (CDCl₃): δ(ppm) 3.79 (3H, s), 4.25-4.35 (2H, m), 6.27 (1H, d,J=2.7), 6.32 (1H, dd, J=8.7, 2.7), 7.24-7.30 (1H, m), 7.75-7.80 (1H, m),8.52 (1H, dd, J=4.8, 1.5), 8.72-8.75 (1H, m);

TLC: R_(f)=0.10 (1:1 hexane/ethyl acetate).

(Step B) Synthesis of 6-methoxy-2-(pyridin-3-yl)-1H-indole

In accordance with the process described in the literature (Knochel etal., Angew. Chem. Int. Ed., vol. 39, pp. 2488-2490, 2000), the titlecompound (337 mg) was obtained using the compound (397 mg; obtained inthe step A of Reference Example 9), potassium-t-butoxide(418 mg) and1-methyl-2-pyrrolidone (14 mL).

¹H-NMR (CDCl₃): δ(ppm) 3.88 (3H, s), 6.80-6.84 (2H, m), 6.91-6.93 (1H,m), 7.32-7.38 (1H, m), 7.52 (1H, d, J=8.4), 7.86-7.92 (1H, m), 8.24-8.34(1H, brs), 8.50-8.54 (1H, m), 8.90-8.93 (1H, m);

TLC: R_(f)=0.10 (1:1 hexane/ethyl acetate).

(Step C) Synthesis of6-methoxy-2-(pyridin-3-yl)-1H-indole-3-carboaldehyde

In accordance with the process described in the literature (Magnus etal., J. Am. Chem. Soc., vol. 110, pp. 2242-2248, 1988) at the reactiontemperature of 60° C., the title compound (573 mg) was obtained usingthe compound (557 mg; synthesized according to the process of the step Bof Reference Example 9), phosphoryl chloride (350 μL) and DMF (5 mL).

¹H-NMR (DMSO-d₆): δ(ppm) 3.83 (3H, s), 6.91 (1H, dd, J=8.7, 2.4), 6.99(1H, d, J=2.4), 7.62 (11H, dd, J=8.1, 4.5), 8.08 (1H, d, J=8.7),8.17-8.22 (1H, m), 8.71-8.75 (1H, m), 8.95 (1H, d, J=2.1), 9.91 (1H, s),12.25-12.47 (1H, brs).

(Step D) Synthesis of 6-methoxy-3-methyl-2-(pyridin-3-yl)-1H-indole

Lithium aluminium hydride (216 mg) was suspended in THF (20 mL), and thecompound (573 mg; obtained in the step C of Reference Example 9) wasgradually added at room temperature. The resulting mixture was heated to40° C. and stirred at the same temperature for 5 minutes. The mixturewas then cooled down to 0° C. Water (216 μL), an aqueous 15% sodiumhydroxide solution (216 μL) and water (648 μL) were added in this order,and the resulting reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (20:1 chloroform/methanol) to yield thetitle compound (506 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.43 (3H, s), 3.86 (3H, s), 6.80-6.88 (2H, m),7.37 (1H, dd, J=8.1, 4.8), 7.48 (1H, d, J=8.7), 7.82-7.86 (1H, m),8.33-8.51 (1H, m), 8.53 (1H, d, J=4.8), 8.81-8.84 (1H,m);

TLC: R_(f)=0.57 (9:1 chloroform/methanol).

(Step E) Synthesis of 6-hydroxy-3-methyl-2-(pyridin-3-yl)-1H-indole

The compound (506 mg; obtained in the step D of Reference Example 9) wasdissolved in methylene chloride (dehydrated, 10 mL), and borontribromide (1 N solution in methylene chloride, 6.4 mL) was addeddropwise under ice-cooling. The resulting mixture was allowed to warm toroom temperature and stirred for 1 hour, followed by ice-cooling. Waterwas then added. The resulting mixture was extracted with chloroform,washed with saturated brine and dried over sodium sulfate. The solventwas distilled off under reduced pressure and the residue was thenpurified by silica gel chromatography (95:5-90:10 chloroform/methanol)to yield the title compound (456 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.48 (3H, s), 6.66 (1H, dd, J=8.4, 1.8), 6.79(1H, d, J=1.8), 7.34 (1H, d, J=8.4), 7.85 (1H, dd, J=8.1, 5.7),8.43-8.48 (1H, m), 8.55 (1H, d, J=5.7), 8.89-8.92 (1H, m);

TLC: R_(f)=0.37 (9:1 chloroform/methanol).

Reference Example 10

Synthesis of ethyl 3-(6-hydroxy-3-methyl-1H-indol-2-yl)propionate

(Step A) Synthesis of 6-methoxy-3-methyl-1H-indole-2-carboaldehyde

In accordance with the process described in the step C of ReferenceExample 9, the title compound (4.60 g) was obtained as a crude productfrom 6-methoxy-3-methyl-1H-indole (3.89 g; synthesized according to theprocess described in the literature (Gan et al., J. Org. Chem., vol. 62,pp. 9298-9304, 1997)), phosphoryl chloride (6.7 mL) and DMF (20 mL).

¹H-NMR (CDCl₃): δ(ppm) 2.60 (3H, s), 3.87 (3H, s), 6.76 (1H, d, J=2.1),6.81 (1H, dd, J=8.7, 2.1), 7.56 (1H, d, J=8.7), 8.67-8.83 (1H, brs),9.90 (1H, s);

TLC: R_(f)=0.39 (2:1 hexane/ethyl acetate).

(Step B) Synthesis of ethyl 3-(6-methoxy-3-methyl-1H-indol-2-yl)acrylate

In accordance with the process described in the literature (Kozikowskiet al., J. Med. Chem., vol. 36, pp. 2908-2920, 1993), the title compound(337 mg) was obtained using the compound (608 mg; obtained in the step Aof Reference Example 10), (carbethoxymethylene)triphenylphosphorane(1.12 g) and toluene (30 mL).

¹H-NMR (CDCl₃): δ(ppm) 1.34 (3H, t, J=7.2), 2.38 (3H, s), 3.85 (3H, s),4.28 (2H, q, J=7.2), 6.02 (1H, d, J=15.9), 6.74-6.79 (2H, m), 7.41-7.46(1H, m), 7.77 (1H, d, J=15.9), 8.06-8.17 (11H, brs);

TLC: R_(f)=0.47 (2:1 hexane/ethyl acetate).

(Step C) Synthesis of ethyl3-(6-methoxy-3-methyl-1H-indol-2-yl)propionate

The compound (337 mg; obtained in the step B of Reference Example 10)was dissolved in the mixture of methanol (6 mL) and THF (2 mL), and 10%palladium/carbon powder (177 mg) was added. The atmosphere in the systemwas replaced with a hydrogen atmosphere, followed by stirring at roomtemperature for 50 minutes. After the atmosphere in the system wasreplaced with an argon atmosphere, the catalyst was filtered and thesolvent contained in the filtrate was distilled off under reducedpressure. The residue was then purified by silica gel columnchromatography (1:1 hexane/ethyl acetate) to yield the title compound(333 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.25 (3H, t, J=7.2), 2.20 (3H, s), 2.60-2.66 (2H,m), 2.96-3.02 (2H, m), 3.83 (3H, s), 4.16 (2H, q, J=7.2), 6.74 (1H, dd,J=8.7, 2.1), 6.79 (1H, d, J=2.1), 7.34 (1H, d, J=8.7), 8.22-8.27 (1H,brs);

TLC: R_(f)=0.47 (2:1 hexane/ethyl acetate).

(Step D) Synthesis of ethyl3-(6-hydroxy-3-methyl-1H-indol-2-yl)propionate

In accordance with the process described in the step E of ReferenceExample 9, the title compound (239 mg) was obtained from the compound(330 mg; obtained in the step C of Reference Example 10), borontribromide (1 N solution in methylene chloride, 3.0 mL) and methylenechloride (dehydrated, 6 mL).

¹H-NMR (CDCl₃): δ(Ppm) 1.25 (3H, t, J=7.2), 2.19 (3H, s), 2.59-2.66 (2H,m), 2.95-2.99 (2H, m), 4.16 (2H, q, J=7.2), 4.81-4.92 (1H, m), 6.64 (1H,dd, J=8.7, 2.1), 6.70-6.73 (1H, m), 7.29 (1H, d, J=8.7), 8.08-8.24 (1H,brs);

TLC: R_(f)=0.16 (2:1 hexane/ethyl acetate).

Reference Example 11

Synthesis of 6-hydroxy-3-methylindazole

(Step A) Synthesis of 1-benzyl-3-methyl-6-methoxyindazole

In accordance with the process described in the literature (S. Caron etal., Synthesis, No. 4, pp. 588-592, 1999), the title compound (4.58 g)was obtained from 2-acetyl-5-methoxyphenylmethanesulfonate (7.05 g),benzylhydrazine dihydrochloride (8.78 g) and acetic acid trihydrate(14.9 g).

¹H-NMR (CDCl₃): δ(ppm) 2.54 (3H, s), 3.80 (3H, s), 5.47 (2H, s), 6.58(1H, d, J=1.9), 6.76 (1H, dd, J=8.8, 1.9), 7.16-7.32 (5H, m), 7.51 (1H,d, J=8.8).

(Step B) Synthesis of 1-benzyl-6-hydroxy-3-methylindazole

Pyridine hydrochloride was prepared by carefully mixing pyridine (100mL) and concentrated hydrochloric acid (100 mL) in a flask equipped witha Liebig condenser and heating the resulting mixture at 180° C. withstirring to remove water. To the mixture, the compound (4.50 g; obtainedin the step A of Reference Example 11) was added, followed by stirringat 180° C. for 2.5 hours. The reaction mixture was poured into ice waterand the pH was adjusted to about 5 with an aqueous sodium hydroxidesolution, followed by extraction with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and the solvent was thendistilled off under reduced pressure. After a mixed solution ofchloroform and methanol (1:1) was added to the residue to form ahomogeneous solution, the solvent was distilled off under reducedpressure. A mixed solvent of hexane and ether (1:1) was added to theresidue to generate a crystal. The crystal thus collected by filtrationwas washed with a mixed solvent of hexane and ether (1:1) and then driedto give the title compound (2.20 g). In addition, the filtrate wasconcentrated and the residue was treated in the same manner to give thetitle compound (688 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.40 (3H, s), 5.41 (11H, s), 6.62 (11H, dd,J=8.5, 1.9), 6.73 (1H, d, J=1.9), 7.15-7.33 (5H, m), 7.47 (1H, d,J=8.5), 9.59 (1H, s).

(Step C) Synthesis of 6-hydroxy-3-methylindazole

The compound (100 mg; obtained in the step B of Reference Example 11)was dissolved in a 0.1 N solution of hydrochloric acid in ethanol (5 mL)and 10% palladium/carbon powder (50 mg) was added. The resulting mixturewas stirred under a hydrogen atmosphere at 40° C. for 5 hours. Thecatalyst was filtered off and the filtrate was concentrated to give thetitle compound (60 mg).

¹H-NMR (CD₃OD): δ(ppm) 2.37 (3H, s), 5.15 (2H, brs), 6.87 (1H, d,J=1.9), 6.99 (1H, dd, J=9.0, 1.9), 7.84 (11H, d, J=9.0).

EXAMPLE 1

Synthesis of ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-i1H-indole-2-carboxylate hydrochloride

(Step A) Synthesis of ethyl 3-methyl-6-hydroxy-1H-indole-2-carboxylate

Ethyl 3-methyl-6-methoxy-1H-indole-2-carboxylate (1.00 g; synthesizedaccording to the disclosures in the literature (Gan et al., J. Org.Chem., vol. 62, pp. 9298-9304, 1997)) was dissolved in methylenechloride (dehydrated, 13 mL), and boron tribromide (1 M/methylenechloride, 17.2 mL) was added dropwise under ice-cooling. The resultingmixture was allowed to warm to room temperature and stirred for 40minutes. The reaction solution was then cooled with ice, followed byaddition of water. The resulting mixture was extracted with chloroform,washed with saturated brine and dried over sodium sulfate. After thesolvent was distilled off under reduced pressure, the residue waspurified by silica gel chromatography (3:1-2:1 hexane/ethyl acetate) toyield the title compound (480 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.42 (3H, t, J=6.9), 2.57 (3H, s), 4.39 (2H, q,J=6.9), 4.86 (1H, s), 6.71 (1H, dd, J=8.7, 2.1), 6.77 (1H, d, J=2.1),7.51 (1H, d, J=8.7), 8.48 (1H, brs).

(Step B) Synthesis of(R)-[3-[2-[N-benzyl-N-[2-(2-ethoxycarbonyl-3-methyl-1H-indol-6-yloxy)ethyl]amino]-1-triethylsilyloxy]ethylphenyl](methylsulfonyl)benzylamine

The compound (87 mg; obtained in the above step A), the compound ofReference Example 1 (262 mg) and 1,1′-azobis(N,N-dimethylformamide)(136mg) were dissolved in THF (5 mL). After the resulting solution wascooled to 0° C., tributyl phosphine (196 μL) was added dropwise,followed by stirring for 10 minutes. The resulting mixture was thenallowed to warm to room temperature and stirred overnight. To thereaction mixture, water (10 mL) was added. The resulting mixture wasextracted with ethyl acetate three times and dried over magnesiumsulfate. After the solvent was distilled off under reduced pressure, theresidue was purified by silica gel chromatography (5:1-2:1 hexane/ethylacetate) to yield the title compound (193 mg) as a light yellow oil.

¹H-NMR (CDCl₃): δ(ppm) 0.38-0.48 (6H, m), 0.81 (9H, t, J=7.8), 1.43 (3H,t, J=7.2), 2.56 (3H, s), 2.68-2.91 (4H, m), 2.87 (3H, s), 3.65-3.82 (4H,m), 4.40 (3H, q, J=7.2), 4.59 (1H, t, J=5.7), 4.77 (1H, d, J=14.7), 4.86(1H, d, J=14.7), 6.53 (1H, d, J=2.1), 6.69 (1H, dd, J=5.7, 2.1),7.10-7.30 (14H, m), 7.47 (1H, d, J=5.7), 8.66-8.72 (1H, brs).

(Step C) Synthesis of(R)-2-[N′-benzyl-N′-[2-(2-ethoxycarbonyl-3-methyl-1H-indol-6-yloxy)ethyl]amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol

The compound (193 mg; obtained in the above step B) was dissolved in THF(5 mL). Acetic acid (115 μL) and tetra-n-butylammonium fluoride (1.0M/THF solution, 2.0 mL) were added and the resulting mixture was stirredat room temperature for 2 hours. To the reaction mixture, a saturatedaqueous sodium hydrogencarbonate solution was added. The resultingmixture was extracted with ethyl acetate three times and dried overmagnesium sulfate. After the solvent was distilled off under reducedpressure, the residue was purified by silica gel chromatography (3:1-2:3hexane/ethyl acetate) to yield the title compound (161 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.42 (3H, t, J=7.2), 2.575 (3H, s), 2.582 (1H, t,J=10.2), 2.80 (1H, dd, J=10.2, 3.6), 2.89 (3H, s), 2.92-3.02 (1H, m),3.06-3.17 (1H, m), 3.68 (1H, d, J=13.5), 3.95 (1H, d, J=13.5), 4.02-4.09(2H, m), 4.40 (2H, q, J=7.2), 4.66 (1H, dd, J=10.2, 3.6), 4.80 (2H, s),6.75 (1H, d, J=2.1), 6.81 (1H, dd, J=9.0, 2.1), 7.09-7.35 (14H, m), 7.52(1H, d, J=9.0), 8.59-8.66 (1H, brs).

(Step D) Synthesis of ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylatehydrochloride

The compound (161 mg; obtained in the above step C) was dissolved inethanol (12 mL) and THF (6 mL). To the resulting solution, 20% palladiumhydroxide/carbon powder (50% moisture, 103 mg) was added. After theatmosphere in the system was replaced with a hydrogen atmosphere, themixture was stirred at 60° C. for 80 minutes. The atmosphere in thesystem was replaced with an argon atmosphere and chloroform (5 mL) wasthen added. After the resulting mixture was filtered and 0.1 Nhydrochloric acid in ethanol (7 mL) was added to the filtrate, thesolvent was distilled off under reduced pressure. Chloroform was addedto the residue. The deposited solid was then collected by filtration anddried to yield the title compound (96 mg).

¹H-NHR (DMSO-d₆): δ(ppm) 1.35 (3H, t, J=6.9), 3.00 (3H, s), 3.01-3.13(1H, m), 3.22-3.34 (1H, m), 3.41-3.50 (2H, m), 4.27-4.37 (4H, m),4.94-5.02 (1H, m), 6.24 (1H, d, J=3.3), 6.79 (1H, dd, J=8.7, 2.1), 6.88(1H, d, J=2.1), 7.10-7.19 (2H, m), 7.28-7.33 (1H, m), 7.36 (1H, t,J=7.5), 7.57 (1H, d, J=8.7), 8.78-9.15 (2H, m), 9.85 (1H, s), 11.33 (1H,s).

TLC: R_(f)=0.33 (free form)(9:1 chloroform/methanol).

EXAMPLE 2

Synthesis of(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-i1H-indole-2-carboxylic acid hydrochloride

The compound (47 mg; obtained in Example 1) was dissolved in methanol(10 mL). An aqueous sodium hydroxide solution (2.0 M, 450 μL) was addedand the resulting mixture was stirred at a temperature of 50 to 55° C.for 4 hours. The reaction mixture was cooled down to room temperatureand 0.1 N hydrochloric acid in ethanol (8 mL) was added. The solvent wasdistilled off under reduced pressure and water (5 mL) was added to theresidue. The solid was collected by filtration and dried to give thetitle compound (28 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 3.00 (3H, s), 3.07 (1H, t, J=12.9), 3.22-3.32(1H, m), 3.41-3.50 (2H, m), 4.26-4.36 (2H, m), 4.92-5.02 (1H, m),6.21-6.27 (1H, m), 6.79 (1H, dd, J=8.7, 2.4), 6.87 (1H, d, J=2.4),7.10-7.19 (2H, m), 7.28-7.34 (1H, m), 7.36 (1H, t, J=7.8), 7.58 (1H, d,J=8.7), 8.74-9.10 (2H, m), 9.85 (1H, s), 11.39 (1H, s);

TLC: R_(f)=0.33 (free form)(9:1 chloroform/methanol).

EXAMPLE 3

Synthesis of ethyl(R)-1-methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-i1H-indole-2-carboxylate hydrochloride

(Step A) Synthesis of(R)-2-[N′-benzyl-N′-[2-(2-ethoxycarbonyl-3-methyl-1-methylindol-6-yloxy)ethyl]amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol

The compound (102 mg; obtained in the step A of Example 1 set forthabove), the compound (314 mg; obtained in Reference Example 1) and1,1′-azobis(N,N-dimethylformamide)(162 mg) were dissolved in THF (5 mL).After the resulting solution was cooled to 0° C., tributyl phosphine(230 μL) was added dropwise, followed by stirring for 10 minutes. Theresulting mixture was then allowed to warm to room temperature andstirred overnight. To the reaction mixture, water (10 mL) was added. Themixture was extracted with ethyl acetate three times and dried overanhydrous magnesium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel chromatography(5:1-3:1 hexane/ethyl acetate). The residue was dissolved in THF (2 mL)and sodium hydride (60% in paraffin, 45 mg) was added, followed bystirring at room temperature for 10 minutes. Methyl iodide (58 μL) wasadded to the reaction mixture and the mixture was stirred at roomtemperature for 20 minutes. The mixture was neutralized with an aqueoushydrochloric acid solution, and then extracted with ethyl acetate fourtimes and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure and the residue was then purified by silica gelchromatography (4:1-2:1 hexane/ethyl acetate). The thus purified residuewas dissolved in THF (1 mL) after the solvent was distilled off. Aceticacid (30 μL) and tetra-n-butylammonium fluoride (1.0 M/THF solution, 0.5mL) were added and the resulting mixture was stirred at room temperaturefor 1 hour. The reaction mixture was neutralized with an aqueous sodiumhydroxide solution, and then extracted with ethyl acetate three timesand dried over magnesium sulfate. After the solvent was distilled offunder reduced pressure, the residue was purified by silica gelchromatography (2:1-2:3 hexane/ethyl acetate) to yield the titlecompound (73 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.43 (3H, t, J=7.2), 2.56 (3H, s), 2.58 (1H, dd,J=12.9, 10.2), 2.80 (1H, dd, J=12.9, 3.6), 2.88 (3H, s), 2.99 (1H, dt,J=14.1, 5.1), 3.15 (1H, dt, J=14.1, 5.4), 3.70 (1H, d, J=13.5), 3.94(3H, s), 3.97 (1H, d, J=13.5), 4.08-4.14 (2H, m), 4.39 (2H, q, J=7.2),4.66 (1H, dd, J=10.2, 3.6), 4.80 (2H, s), 6.68 (1H, d, J=2.1), 6.82 (1H,dd, J=9.0, 2.1), 7.12 (1H, dt, J=7.5, 2.1), 7.17-7.36 (13H, m), 7.53(1H, d, J=9.0).

(Step B) Synthesis of ethyl(R)-1-methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylatehydrochloride

The compound (73 mg; obtained in the above step A) was dissolved inethanol (10 mL) and THF (5 mL). To the resulting solution, 20% palladiumhydroxide/carbon powder (50% moisture, 72 mg) was added. After theatmosphere in the system was replaced with a hydrogen atmosphere, themixture was stirred at 60° C. for 2 hours. The atmosphere in the systemwas replaced with an argon atmosphere and chloroform (5 mL) was thenadded. After the resulting mixture was filtered and 0.1 N hydrochloricacid in ethanol (7 mL) was added to the filtrate, the solvent wasdistilled off under reduced pressure. A small amount of chloroform anddiethyl ether was added to the residue. The deposited solid was thencollected by filtration and dried to yield the title compound (42 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 1.35 (3H, t, J=7.2), 2.98-3.16 (1H, m), 3.00(3H, s), 3.20-3.32 (1H, m), 3.39-3.54 (2H, m), 3.92 (3H, s), 4.32 (2H,q, J=7.2), 4.36-4.45 (2H, m), 4.96-5.05 (1H, m), 6.26 (1H, d, J=3.9),6.83 (1H, dd, J=8.7, 2.1), 7.09 (1H, d, J=2.1), 7.10-7.19 (2H, m),7.29-7.33 (1H, m), 7.36 (1H, t, J=7.5), 7.61 (1H, d, J=8.7), 8.87-9.07(1H, brs), 9.10-9.28 (1H, brs), 9.85 (1H, s);

TLC: R_(f)=0.37 (free form)(9:1 chloroform/methanol).

EXAMPLE 4

Synthesis of(R)-1-methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylicacid hydrochloride

In accordance with the process described in Example 2, the titlecompound (9.6 mg) was obtained from the compound of Example 3.

According to the processes described in Examples 1 to 4, the compounds(Examples 5 to 83) listed in Table 1 were synthesized. Among thecompounds of Table 1, the compounds of Examples 13, 14, 16, 20, 24 and72 to 83 were analyzed by liquid chromatograph/mass spectrometry(LC-MS). The results obtained from the analyses showed that theobjective compounds of said Examples were produced. TABLE 1 (I)

(wherein Z² to Z⁶ represent a carbon atom) Ex. R¹ R² R⁵ Y X R⁶ R⁷ Z¹ 5 HNHSO₂Me H 6-O NH Me CO₂Et C 6 H NHSO₂Me H 6-O NH Me CO₂H C 7 H NHSO₂Me H6-O NH Me CH₂OH C 8 H NHSO₂Me H 6-O NH Me CH₂NMe₂ C 9 H NHSO₂Me H 6-O NHMe CH₂CO₂Et C 10 H NHSO₂Me H 6-O NH Me CH₂CO₂H C 11 H NHSO₂Me H 6-O NHMe CH═CHCO₂Et C 12 H NHSO₂Me H 6-O NH Me CH═CHCO₂H C 13 H NHSO₂Me H 6-ONH Me CH₂CH₂CO₂Et C 14 H NHSO₂Me H 6-O NH Me CH₂CH₂CO₂H C 15 H NHSO₂Me H6-O NH Me CH₂CH₂NH₂ C 16 H NHSO₂Me H 6-O NH Me CH₂CH₂NMe₂ C 17 H NHSO₂MeH 6-O NH Me COCH₃ C 18 H NHSO₂Me H 6-O NH Et CH₂CO₂Et C 19 H NHSO₂Me H6-O NH Et CH₂CO₂H C 20 H NHSO₂Me H 6-O NH Et CH₂CH₂CO₂Et C 21 H NHSO₂MeH 6-O NH Et CH₂CH₂CO₂H C 22 H NHSO₂Me H 6-O NH Ph CH₂CO₂Et C 23 HNHSO₂Me H 6-O NH Ph CH₂CO₂H C 24 H NHSO₂Me H 6-O NH Ph CH₂CH₂CO₂H C 252-Cl NHSO₂Me H 6-O NH Me CH₂CO₂Et C 26 2-Cl NHSO₂Me H 6-O NH Me CH₂CO₂HC 27 2-F NHSO₂Me H 6-O NH Me CH₂CO₂Et C 28 2-F NHSO₂Me H 6-O NH MeCH₂CO₂H C 29 2-OH SO₂NHMe H 6-O NH Me CH₂CO₂Et C 30 H NHSO₂Me H 6-O NHCH₂CH₂OMe CH₂CO₂H C 31 H NHSO₂Me H 6-O NH CH₂CH₂OMe CH₂CH₂CO₂H C 32 HRHSO₂Me H 6-O NH CH₂CH₂OMe Me C 33 H NHSO₂Me H 6-O NH CH₂CH₂OMe Et C 34H NHSO₂Me H 6-NH NH CO₂Et Me C 35 H NHSO₂Me H 6-NH NH CO₂H Me C 36 2-ClNHSO₂Me H 6-O NH CH₂CO₂Et Me C 37 2-F NHSO₂Me H 6-O NH CH₂CO₂Et Me C 382-F NHSO₂Me (R)—Me 6-O NH CO₂Et Me C 39 H NHSO₂Me H 6-O O CO₂Et Me C 40H NHSO₂Me H 6-O O CO₂H Me C 41 H NHSO₂Me H 6-O O CH₂CO₂Et Me C 42 HNHSO₂Me H 6-O O CH₂CO₂H Me C 43 H NHSO₂Me H 6-O O Me CH₂CO₂Et C 44 HNHSO₂Me H 6-O O Me CH₂CO₂H C 45 H NHSO₂Me H 6-O O Me CH₂CH₂CO₂Et C 46 HNHSO₂Me H 6-O O Me CH₂CH₂CO₂H C 47 H NHSO₂Me H 6-O O Ph CH₂CO₂Et C 48 HNHSO₂Me H 6-O O Ph CH₂CO₂H C 49 H NHSO₂Me H 6-O O Ph CH₂CH₂CO₂Et C 50 HNHSO₂Me H 6-O O Ph CH₂CH₂CO₂H C 51 H NHSO₂Me H 6-O S Ph CH₂CO₂Et C 52 HNHSO₂Me H 6-O S Ph CH₂CH₂CO₂Et C 53 H NHSO₂Me H 6-O O CON(CH₂)₄ H C 54 HNHSO₂Me H 6-O O Isoxazol-3-yl H C 55 H NHSO₂Me H 5-O NH CO₂Et Me C Ex.R¹ R² R⁵ Y X R⁶ R⁷ Z² 56 H NHSO₂Me H 6-O NMe CO₂Et H C 57 H NHSO₂Me H6-O NMe CO₂H H C 58 H NHSO₂Me H 6-O NCH₂Ph CO₂H H C 59 H NHSO₂Me H 6-ONCH₂Ph CH₂CO₂H H C 60 H NHSO₂Me H 6-O NCH₂Ph CH₂CH₂CO₂H H C 61 H NHSO₂MeH 6-O NCH₂Ph CH₂CH₂NMe₂ H C 62 H NHSO₂Me H 6-O NCH₂Ph—NHMs-m CO₂H H C 63H NHSO₂Me H 6-O NCH₂Ph—NHMs-m CH₂CO₂H H C 64 H NHSO₂Me H 6-ONCH₂Ph—NHMs-m CH₂CH₂CO₂H H C 65 H NHSO₂Me H 6-O NCH₂Ph—NHMs-m CH₂CH₂NMe₂H C 66 H NHSO₂Me H 6-O NCH₂Ph—NHMs-p CO₂H H C 67 H NHSO₂Me H 6-ONCH₂Ph—NHMs-p CH₂CO₂H H C 68 H NHSO₂Me H 6-O NCH₂Ph—NHMs-p CH₂CH₂CO₂H HC 69 H NHSO₂Me H 6-O NCH₂Ph—NHMs-p CH₂CH₂NMe₂ H C 70 H NHSO₂Me H 6-O NHCF₃ CF₃ C 71 H NHSO₂Me H 6-O NH CO₂H — N 72 H NHSO₂Me H 6-O NH 3-pyridylMe C 73 H NHSO₂Me H 6-O NH 3-pyridyl Et C 74 H NHSO₂Me H 6-O NH4-pyridyl CH₃ C 75 H NHSO₂Me H 6-O NH N-Boc-3- Me C piperidinyl 76 HNHSO₂Me H 6-O NH 3-piperidinyl Me C 77 H NHSO₂Me H 6-O NH Me CH₂CH₂NHAcC 78 H NHSO₂Me H 6-O NH Ph CH₂CH₂CO₂Et C 79 2-F NHSO₂Me H 6-O NH3-pyridyl Me C 80 2-F NHSO₂Me H 6-O NH CH₂CH₂CO₂Et Me C 81 H NHSO₂Me H6-O NH CH₂CH₂CONMe₂ Me C 82 H NHSO₂Me H 6-O NH CH₂CH₂CO₂Et Me C 83 HNHSO₂Me H 6-O NH CH₂CO₂Et Me C

Examples 84 and 85

Synthesis of(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride (Example 84) Synthesis of(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride (Example 85)

(Step A) Synthesis of(R)—N-benzyl-N-[3-[2-[N′-benzyl-2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

In accordance with the process described in the step B of Example 1, thetitle compound (1.58 g) was obtained from the compound (1.27 g;described in Reference Example 1), the compound (530 mg; obtained in thestep B of Reference Example 11), 1,1′-azobis(N,N-dimethylformamide)(860mg) and triphenylphosphine (1.31 g).

¹H-NMR (CDCl₃): δ(ppm) 0.37-0.46 (6H, m), 0.80 (9H, t, J=7.9), 2.52 (3H,s), 2.71-2.87 (2H, m), 2.80 (3H, s), 3.64-3.70 (4H, m), 4.56 (1H, t,J=6.0), 4.72-4.83 (2H, m), 5.44 (2H, m), 6.42 (1H, d, J=2.2), 7.67 (1H,dd, J=8.8, 2.2), 7.02-7.35 (19H, m), 7.47 (1H, d, J=8.8).

(Step B) Synthesis of(R)—N-benzyl-N-[3-[2-[N′-benzyl-2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

In accordance with the process described in the step C of Example 1, thetitle compound (1.05 g) was obtained from the compound (1.58 g; obtainedin the above step A).

¹H-NMR (CDCl₃): δ(ppm) 2.51-2.58 (1H, m), 2.54 (3H, s), 2.74-2.80 (1H,m), 2.88 (3H, s), 2.87-3.14 (2H, m), 3.66 (1H, d, J=13.7), 3.92 (1H, d,J=13.7), 3.98 (2H, t, J=5.2), 4.63 (1H, dd, J=9.8, 3.0), 4.80 (2H, s),5.46 (2H, s), 6.55 (1H, d, J=1.9), 6.78 (1H, dd, J=8.5, 1.9), 7.10-7.35(15H, m), 7.52 (1H, d, J=8.5).

(Step C) Syntheses of(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride and(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (740 mg; obtained in the above step B) was dissolved in amixed solvent of THF (5 mL) and methanol (5 mL). To the resultingsolution, 20% palladium hydroxide/carbon powder (50% moisture, 186 mg)was added. After the atmosphere in the system was replaced with ahydrogen atmosphere, the mixture was stirred at 50° C. for 6 hours. Thecatalyst was separated by filtration and the filtrate was concentratedunder reduced pressure. The compound of Example 85 was obtained bypurifying 50 mg aliquot of the residue. The remainder of the residue wasdissolved in a 0.1 N hydrochloric acid solution in ethanol (13 mL) and20% palladium hydroxide/carbon powder (50% moisture, 203 mg) was added.After the atmosphere in the system was replaced with a hydrogenatmosphere, the mixture was stirred at 50° C. for 1 hour. After thegenerated precipitate was dissolved by adding a small amount ofconcentrated ammonia water, the catalyst was separated by filtration andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in ethanol and a 0.1 N hydrochloric acid solution in ethanolwas added. The generated crystal was filtered, washed with ether andthen dried to yield the compound (274 mg) of Example 84.

(Example 84):(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride; ¹H-NMR (DMSO-d₆): δ(ppm) 2.45 (3H, s), 3.00 (3H, s),3.02-3.32 (2H, m), 3.42-3.50 (2H, m), 4.32-4.38 (2H, m), 4.79 (2H, br),4.98-5.02 (1H, m), 6.78 (1H, dd, J=8.8, 2.2), 6.91 (1H, d, J=2.2),7.12-7.17 (2H, m), 7.30-7.38 (2H, m), 7.61 (1H, d, J=8.8), 8.99 (11H,br), 9.26 (1H, br), 9.85 (1H, s);

(Example 85):(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride; ¹H-NMR (DMSO-d₆): δ(ppm) 2.43 (3H, s), 3.00 (3H, s),3.01-3.49 (4H, m), 4.34-4.39 (2H, m), 4.96-5.02 (1H, m), 5.52 (2H, s),6.79 (1H, dd, J=8.8, 1.9), 7.11-7.38 (11H, m), 7.61 (1H, d, J=8.8), 8.96(1H, br), 9.13 (1H, br), 9.85 (11H, s).

According to the processes described in Examples 84 and 85, thecompounds (Examples 86 to 90) listed in Table 2 were synthesized. Thesecompounds were analyzed by liquid chromatograph/mass spectrometry(LC-MS). The results obtained from the analyses showed that theobjective compounds of said Examples were produced. TABLE 2 (I)

(wherein Z¹ and Z³ to Z⁶ represent a carbon atom; Z² represents anitrogen atom; and R⁶ is absent) Ex. R¹ R² R⁵ Y X R⁷ 86 H NHSO₂Me H 6-ONH OMe 87 4-F NHSO₂Me H 6-O NH Me 88 2-Cl NHSO₂Me H 6-O NH Me 89 OHSO₂NHMe H 6-O NH Me 90 H NHSO₂Me (R)—Me 6-O NH Me[Test Example 1]Human β3-Agonist Activities

Human β3-agonist activities were determined using CHO (Chinese hamsterovary) cells transfected with pcDNA3 (mfd. by Invitrogen) to which humanβ3 gene had been inserted. Human β3 fragment was first obtained fromhuman adipose tissue cDNA (mfd. by Clonetech) by PCR using the primer ofβ3 (Krief, et al., J. Clin. Invest., vol. 91, pp. 344-349 (1993)). Thehuman β3 fragment thus obtained was used as a probe to obtain the fulllength human P3 gene from a human genomic library (mfd. by Clonetech).The above cells were cultured in a Ham F-12 medium supplemented with 10%fetal bovine serum, 400 μg/mL geneticin (Gibco BRL), 100 U/mL penicillinand 100 μg/mL streptomycin. After placing these cells (5×10⁵) into a6-well plate and culturing them for 24 hours, they were allowed to standon a serum-free Ham F-12 medium for 2 hours. The compound was firstdissolved in DMSO, repeatedly diluted by ten times with Ham F-12supplemented with 1 mM isobutylmethyl-xanthine and 1 mM ascorbic acid toa final concentration of from 10⁻⁵ to 10⁻¹² M, and then added to thecells. After the cells were cultured for 30 minutes, the medium wasremoved, followed by addition of 0.5 mL of 1 N NaOH. The medium wasallowed to stand for 20 minutes and then 0.5 mL of 1 N acetic acid wasadded to the medium. The medium was stirred and then centrifuged,followed by quantitating cAMP with cAMP EIA kit (mfd. by Cayman). Withrespect to several compounds among the compounds described in Examples,their EC₅₀ values were indicated in Table 3. Isoproterenol was purchasedfrom RBI (Research Biochemicals International). It has been found thatthe compounds of the present invention have human β3-agonist activities.TABLE 3 Intrinsic Compound EC₅₀(nM) activity* % Example 1  15 97 Example2  18 124 Example 13 23 38 Example 20 32 55 Example 72 2.8 105 Example73 3.5 75 Example 74 3.9 71 Example 75 4.4 79 Example 76 21 76 Example78 43 71 Example 79 3.4 65 Example 80 2.8 63 Example 81 2.8 77 Example82 1.4 81 Example 84 12 81 Example 86 26 64 Example 87 24 56 Example 884.7 52 Example 89 11 80*Relative activities (%) as compared with isoproterenol.[Test Example 2]Action on the Heart

The heart was excised from a male guinea pig weighing 180-250 g toprepare a specimen of the right atrium. The specimen was set in an organbath filled with a Krebs solution which had been aerated with a mixedgas of 5% CO₂/95% O₂. The automaticity was determined using a isometrictransducer (NIHON KOHDEN TB-611T) connected to a polygraph (NIHON KOHDENMR-6000). The present compounds described in Examples have a higher ED₅₀value than that of β3. Therefore, these compounds were expected to haveselective actions and hardly induce an increase of the heart rate, thatis, to entail little side effects.

[Test Example 3]

Pharmacological Effect on a Transgenic Mouse Expressing Human β3

A transgenic mouse expressing human β3 was prepared according to themethod reported by Hogan et al. (A Laboratory Manual, 2nd Ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) by linkingmouse β3 promoter to upstream of human β3 gene used in Test Example 1.The mouse expressed human β3 gene in an organ which expresses mouse β3.

After fasted for four hours, the transgenic mouse is orally dosed with acompound of the present invention dissolved in 10%hydroxypropyl-α-cyclodextrin (Aldrich) at a dose of 0.1 mL/10 g bodyweight. After 0 minute, 30 minutes, 1 hour and 2 hours, blood samplesare collected from venous plexus of the eyeground. A blood glucose levelwas determined by measuring the serum glucose concentration in thesample using Glucose Test B Test Wako (Wako Pure Chemical Industries). Afree fatty acid level was measured using NEFA HA Test Wako (Wako PureChemical Industries). It was found that compounds of the presentinvention exhibit hypoglycemic activity and lipolytic activity withincreasing the blood free fatty acid concentration.

The thermogenesis was measured with OXYMAX System (Columbus) accordingto the method reported by Largis et al. (Drug Development Research, vol.32, pp. 69-76 (1994)). The measurement of thermogenesis carried outafter the oral administration of a compound of the present inventionshowed the compounds of the present invention to posses thermogenesisincreasing activities.

The results set forth above demonstrate that compounds of the presentinvention are effective in treating obesity and diabetes.

[Test Example 4]

Therapeutic Effect for Urinary Incontinence

The contractive power of human urinary bladder detrusor was determinedaccording to the method reported by Takeda M. et al. (J. Pharm. Exp.Ther. 288, pp. 1367-1373 (1999)). That is, compounds of the presentinvention were tested for their relaxant effects using the human urinarybladder detrusor in the constricted condition induced by carbachol(0.5×10⁻⁶ M). The fact that the urinary bladder detrusor was allowed torelax by the present compounds at 10⁻⁵ M suggests the effectiveness ofthe present compounds against urinary incontinence.

[Test Example 5]

Toxicity Test

Each of the present compounds synthesized in Examples 1 and 2 was orallyadministered to 6-week old male ddy mice (CHARLES RIVER JAPAN) at 100mg/kg. The fact that none of eight animals were found to be dead showedthese compounds to have a low toxicity. The other compounds, which gotthe same results, were also shown to have a low toxicity.

All the publications, patents and patent applications cited in thisspecification are incorporated herein in their entities by reference.

Industrial Utility

Compounds of the present invention are novel compounds. They areexpected to be a compound which is unlikely to induce any side effectdue to drug interactions, since they have a high human β3-adrenoreceptorstimulating activity and a low drug metabolizing enzyme inhibitingactivity. Therefore, compounds of the present invention are useful as amedicine for treating and preventing β3-adrenoreceptor associateddiseases including diabetes, obesity and hyperlipidemia. Compounds ofthe present invention are also useful as a medicine for treating andpreventing fatty liver, urinary incontinence and others.

1. A compound of the general formula (I):

or a salt thereof, wherein R¹ represents a hydrogen atom, a hydroxylgroup or a halogen atom; R² represents NHSO₂R³ or SO₂NR⁴R^(4′); R³represents a (C₁-C₆)alkyl group, a benzyl group, a phenyl group orNR⁴R^(4′); R⁴ and R^(4′) may be the same or different and eachindependently represents a hydrogen atom or a (C₁-C₆)alkyl group; R⁵represents a hydrogen atom or a (C₁-C₆)alkyl group; R⁶ and R⁷ may be thesame or different and each independently represents a hydrogen atom, a(C₁-C₆)alkyl group, a (C₁-C₆)alkyl group optionally substituted with oneor more halogen atoms, an optionally substituted —(CH₂)_(n)-phenylgroup, —CH═CH—CO₂R⁵ or —(CH₂)_(n)—R⁸; R⁸ represents OR⁵, CN, NR⁴¹R^(4′),CO₂R⁵, SO₃R⁵, SO₂ (C₁-C₆) alkyl, SO₂NR⁴¹R^(41′), C(═O)R⁵,C(═O)NR⁴¹R^(41′) or NR⁵¹COR⁵, wherein R⁵ is as defined above; R⁵¹represents a hydrogen atom or a (C₁-C₆)alkyl group; R⁴¹ and R^(41′) maybe the same or different and each independently represents a hydrogenatom, a (C₁-C₆)alkyl group or a (C₃-C₆)cycloalkyl group, or R⁴¹ andR^(41′) taken together represent a (C₂-C₆)alkylene group; or R⁸ is aheterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, thiazolyl,oxazolyl, imidazolyl, triazolyl, 1,2,4-oxadiazolyl, isoxazolyl,tetrazolyl, pyrazolyl, hexamethyleneiminyl, piperidinyl andpyrrolidinyl, wherein one of the ring nitrogen atoms of imidazolyl,triazolyl and tetrazolyl may be optionally substituted with a(C₁-C₆)alkyl group which is optionally substituted with one or morehalogen atoms; wherein with respect to one or more of the ring carbonatoms of the each heterocycle, each of them may be optionallysubstituted with one or more substituents which are independentlyselected from hydrogen, a (C₁-C₆)alkyl group optionally substituted withone or more halogen atoms, a halogen atom, nitro, cyano and(CH₂)_(n)—R⁹; and wherein the ring nitrogen atom of hexamethyleneiminyl,piperidinyl and pyrrolidinyl may be substituted with a (C₁-C₆)alkylgroup, a (C₃-C₆)cycloalkyl group, COR⁵, COOR⁵, CONR⁴R⁴ or SO₂R⁵; R⁹represents NR⁴R⁴, CO₂R⁵, C(═O)—NR⁴R⁴, OR⁵, SO₃R⁵, SO₂(C₁-C₆)alkyl orSO₂NR⁴R⁴, wherein R⁵, R⁴ and R⁴ are as defined above; provided that thecombinations of R⁶ and R⁷ are excluded in which R⁶ and R⁷ are the sameor different and are each selected from a hydrogen atom, (C₁-C₆)alkyland an optionally substituted —(CH₂)_(m)-phenyl group wherein m is 0 or1; X represents NR¹⁰, an oxygen atom or a sulfur atom; Y represents anoxygen atom, NH, a sulfur atom or a methylene group; all of Z¹ to Z⁶represent a carbon atom; or one of them represents a nitrogen atom andthe others represent a carbon atom; provided that when Z¹ is a nitrogenatom, then R⁷ is absent; when Z² is a nitrogen atom, then R⁶ is absent;and when any one of Z³ to Z⁶ is a nitrogen atom, then no linkage isgenerated between Y and the corresponding Z; R¹⁰ represents a hydrogenatom, an optionally substituted —(CH₂)_(n)-phenyl group, a—(C₁-C₁₀)alkyl group or —(CH₂)_(n)—R⁸, wherein R⁸ is as defined above; nis an integer of 0 to 6; *1 represents an asymmetric carbon atom; and *2represents an asymmetric carbon atom when R⁵ is other than a hydrogenatom.
 2. A compound as claimed in claim 1 having the general formula(I), wherein Z¹ is a nitrogen atom or a carbon atom; and each of Z² toZ⁶ is a carbon atom, or a salt thereof.
 3. A compound as claimed inclaim 1 having the general formula (I), wherein R⁸ is OR⁵, CN,NR⁴¹R^(41′), CO₂R⁵, SO₃R⁵, SO₂(C₁-C₆)alkyl, SO₂NR⁴¹, R^(41′), C(═O)R⁵ orC(═O)NR⁴¹R^(41′), wherein R⁵ is as defined above; and R⁴¹ and R^(41′)may be the same or different and are each independently a hydrogen atomor a (C₁-C₆)alkyl group, or R⁴¹ and R^(41′) taken together represent a(C₂-C₆)alkylene group; or R⁸ is a heterocycle selected from pyridyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,1,2,4-oxadiazolyl, isoxazolyl, tetrazolyl and pyrazolyl, wherein one ofthe ring nitrogen atoms of imidazolyl, triazolyl and tetrazolyl may beoptionally substituted with a (C₁-C₆)alkyl group which is optionallysubstituted with one or more halogen atoms; wherein with respect to oneor more of the ring carbon atoms of the each heterocycle, each of themmay be optionally substituted with one or more substituents which areindependently selected from hydrogen, a (C₁-C₆)alkyl group optionallysubstituted with one or more halogen atoms, a halogen atom, nitro, cyanoand —(CH₂)_(n)—R⁹, wherein R⁹ is as defined above, or a salt thereof. 4.A compound as claimed in claim 1 having the general formula (I), whereinZ² is a nitrogen atom; R⁶ is absent; and each of Z¹ and Z³ to Z⁶ is acarbon atom, or a salt thereof.
 5. A compound as claimed in claim 1having the general formula (I), wherein R¹ is present on para position(2-position) with respect to the amino alcohol side chain, or a saltthereof.
 6. A compound as claimed in claim 1 having the general formula(I), wherein Y is an oxygen atom, NH or a sulfur atom, or a saltthereof.
 7. A compound as claimed in claim 1 having the general formula(I), wherein X is NH, an oxygen atom or a sulfur atom, or a saltthereof.
 8. A compound as claimed in claim 1, which is a compoundselected from the group consisting of: ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylicacid;(R)-N-[3-[2-[2-(3-hydroxymethyl-2-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(N′,N′-dimethylamino)methyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylate;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylicacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionate;(R)-3-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[3-(2-aminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-N′,N′-dimethylamino)ethyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-acetyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(4-hydroxy-3-methylsulfamoyl)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]aceticacid;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[2-(2-methoxyethyl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-ethyl-2-(2-methoxyethyl)-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R,R)-6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]propoxy]-3-methyl-1H-indole-2-carboxylate;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylicacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]acetate;ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]propionate;(R)-N-[3-[2-[2-(2-pyrrolidylcarbonylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(isoxazol-3-yl)benzofuran-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-5-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-1-benzyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[3-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[4-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-N-[3-[2-[2-(2,3-ditrifluoromethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-ethyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-4-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(N′-t-butyloxycarbonylpiperidin-3-yl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[1-hydroxy-2-(3-methyl-2-piperidin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-acetylaminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-hydroxy-2-(3-methylsulfonylaminophenyl)ethylamino]ethoxy]-3-phenyl-1H-indol-2-yl]propionate;(R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-(4-fluoro-3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]propionate;(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethyl]amino]ethoxy]-1H-indol-2-yl]-N,N-dimethylpropionamide;ethyl(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]propionate;ethyl(R)-2-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]acetate;(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-methoxyindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;(R)-N-methyl-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamide;and(R,R)-N-[3-[1-hydroxy-2-[1-methyl-2-(3-methylindazol-6-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide,or a salt thereof.
 9. A medicine comprising a compound of claim 1 or asalt thereof as an active ingredient.
 10. A method for treating orpreventing in a subject any one of diabetes, obesity, hyperlipidemia andurinary incontinence, comprising: administering to said subject aneffective amount of the compound according to claim
 9. 11. A compound asclaimed in claim 2 having the general formula (I), wherein R⁸ is OR⁵,CN, NR⁴¹R^(41′), CO₂R⁵, SO₃R⁵, SO₂(C₁-C₆)alkyl, SO₂NR⁴¹R^(41′), C(═O)R⁵or C(═O)NR⁴¹R^(41′), wherein R⁵ is as defined above; and R⁴¹ and R^(41′)may be the same or different and are each independently a hydrogen atomor a (C₁-C₆)alkyl group, or R⁴¹ and R⁴¹′ taken together represent a(C₂-C₆)alkylene group; or R⁸ is a heterocycle selected from pyridyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,1,2,4-oxadiazolyl, isoxazolyl, tetrazolyl and pyrazolyl, wherein one ofthe ring nitrogen atoms of imidazolyl, triazolyl and tetrazolyl may beoptionally substituted with a (C₁-C₆)alkyl group which is optionallysubstituted with one or more halogen atoms; wherein with respect to oneor more of the ring carbon atoms of the each heterocycle, each of themmay be optionally substituted with one or more substituents which areindependently selected from hydrogen, a (C₁-C₆)alkyl group optionallysubstituted with one or more halogen atoms, a halogen atom, nitro, cyanoand —(CH₂)_(n)—R⁹, wherein R⁹ is as defined above, or a salt thereof.12. A compound as claimed in claim 2 having the general formula (I),wherein R¹ is present on para position (2-position) with respect to theamino alcohol side chain, or a salt thereof.
 13. A compound as claimedin claim 3 having the general formula (I), wherein R¹ is present on paraposition (2-position) with respect to the amino alcohol side chain, or asalt thereof.
 14. A compound as claimed in claim 4 having the generalformula (I), wherein R¹ is present on para position (2-position) withrespect to the amino alcohol side chain, or a salt thereof.
 15. Acompound as claimed in claim 2 having the general formula (I), wherein Yis an oxygen atom, NH or a sulfur atom, or a salt thereof.
 16. Acompound as claimed in claim 3 having the general formula (I), wherein Yis an oxygen atom, NH or a sulfur atom, or a salt thereof.
 17. Acompound as claimed in claim 4 having the general formula (I), wherein Yis an oxygen atom, NH or a sulfur atom, or a salt thereof.
 18. Acompound as claimed in claim 5 having the general formula (I), wherein Yis an oxygen atom, NH or a sulfur atom, or a salt thereof.
 19. Acompound as claimed in claim 2, which is a compound selected from thegroup consisting of: ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylicacid;(R)-N-[3-[2-[2-(3-hydroxymethyl-2-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(N′,N′-dimethylamino)methyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylate;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylicacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionate;(R)-3-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[3-(2-aminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-N′,N′-dimethylamino)ethyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-acetyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(4-hydroxy-3-methylsulfamoyl)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]aceticacid;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[2-(2-methoxyethyl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-ethyl-2-(2-methoxyethyl)-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R,R)-6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]propoxy]-3-methyl-1H-indole-2-carboxylate;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylicacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]acetate;ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]propionate;(R)-N-[3-[2-[2-(2-pyrrolidylcarbonylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(isoxazol-3-yl)benzofuran-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-5-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-1-benzyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[3-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[4-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-N-[3-[2-[2-(2,3-ditrifluoromethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-ethyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-4-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(N′-t-butyloxycarbonylpiperidin-3-yl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[1-hydroxy-2-(3-methyl-2-piperidin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-acetylaminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-hydroxy-2-(3-methylsulfonylaminophenyl)ethylamino]ethoxy]-3-phenyl-1H-indol-2-yl]propionate;(R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-(4-fluoro-3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]propionate;(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethyl]amino]ethoxy]-1H-indol-2-yl]-N,N-dimethylpropionamide;ethyl(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]propionate;ethyl(R)-2-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]acetate;(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-methoxyindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;(R)—N-methyl-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamide;and(R,R)-N-[3-[1-hydroxy-2-[1-methyl-2-(3-methylindazol-6-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide,or a salt thereof.
 20. A compound as claimed in claim 4, which is acompound selected from the group consisting of: ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indole-3-carboxylicacid;(R)-N-[3-[2-[2-(3-hydroxymethyl-2-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(N′,N′-dimethylamino)methyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylate;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acrylicacid; ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionate;(R)-3-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[3-(2-aminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-N′,N′-dimethylamino)ethyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-acetyl-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-ethyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methanesulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]acetate;(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(4-hydroxy-3-methylsulfamoyl)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-1H-indol-3-yl]aceticacid;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]aceticacid;(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-(2-methoxyethyl)-1H-indol-3-yl]propionicacid;(R)-N-[3-[2-[2-[2-(2-methoxyethyl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-ethyl-2-(2-methoxyethyl)-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethylamino]-3-methyl-1H-indole-2-carboxylicacid; ethyl(R)-[6-[2-[2-(4-chloro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R)-[6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]acetate;ethyl(R,R)-6-[2-[2-(4-fluoro-3-methylsulfonylamino)phenyl-2-hydroxyethylamino]propoxy]-3-methyl-1H-indole-2-carboxylate;ethyl(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylate;(R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-benzofuran-2-carboxylicacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]acetate;(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-methyl-benzofuran-3-yl]aceticacid; ethyl(R)-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]acetate;ethyl(R)-3-[6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-2-phenylbenzothiophen-3-yl]propionate;(R)-N-[3-[2-[2-(2-pyrrolidylcarbonylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(isoxazol-3-yl)benzofuran-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-5-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate;(R)-1-benzyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[3-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-1-[4-(N′-methylsulfonylamino)phenyl]methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-1H-indole-2-carboxylicacid;(R)-N-[3-[2-[2-(2,3-ditrifluoromethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-ethyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[1-hydroxy-2-[2-(3-methyl-2-pyridin-4-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[2-(N′-t-butyloxycarbonylpiperidin-3-yl)-3-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[1-hydroxy-2-(3-methyl-2-piperidin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-[3-(2-acetylaminoethyl)-2-methyl-1H-indol-6-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-hydroxy-2-(3-methylsulfonylaminophenyl)ethylamino]ethoxy]-3-phenyl-1H-indol-2-yl]propionate;(R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(3-methyl-2-pyridin-3-yl-1H-indol-6-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;ethyl(R)-3-[6-[2-[2-(4-fluoro-3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indol-2-yl]propionate;(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethyl]amino]ethoxy]-1H-indol-2-yl]-N,N-dimethylpropionamide;ethyl(R)-3-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]propionate;ethyl(R)-2-[3-methyl-6-[2-[2-(3-methylsulfonylaminophenyl)-2-hydroxyethylamino]ethoxy]-1H-indol-2-yl]acetate;(R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[3-[2-[2-(3-methoxyindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;(R)-N-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;(R)-N-methyl-[5-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamide;and(R,R)-N-[3-[1-hydroxy-2-[1-methyl-2-(3-methylindazol-6-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide,or a salt thereof.